Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects

ABSTRACT

Dosage forms, drug delivery systems, and methods related to sustained release of dextromethorphan or improved therapeutic effects are disclosed. Typically, bupropion or a related compound is orally administered to a human being to be treated with, or being treated with, dextromethorphan.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 16/127,832, filed Sep. 11, 2018, which is a continuation ofU.S. patent application Ser. No. 15/647,069, filed Jul. 11, 2017, nowU.S. Pat. No. 10,105,327; which is a continuation-in-part of U.S. patentapplication Ser. No. 15/280,938, filed Sep. 29, 2016, now U.S. Pat. No.9,707,191; which is a continuation-in-part of U.S. patent applicationSer. No. 15/182,253, filed Jun. 14, 2016, now U.S. Pat. No. 9,474,731;which is a continuation-in-part of U.S. patent application Ser. No.14/978,976, filed Dec. 22, 2015, now U.S. Pat. No. 9,370,513; which is adivision of U.S. patent application Ser. No. 14/554,947, filed Nov. 26,2014, now abandoned; which is a continuation of U.S. patent applicationSer. No. 14/550,618, filed Nov. 21, 2014, now U.S. Pat. No. 9,198,905;U.S. patent application Ser. No. 15/647,069 is also a continuation ofU.S. patent application Ser. No. 15/599,163, filed May 18, 2017, nowU.S. Pat. No. 9,968,568; which is a continuation-in-part of U.S. patentapplication Ser. No. 15/206,057, filed Jul. 8, 2016, now U.S. Pat. No.9,861,595; which is a continuation-in-part of U.S. patent applicationSer. No. 14/602,177, filed Jan. 21, 2015, now U.S. Pat. No. 9,402,843;which is a continuation-in-part of U.S. patent application Ser. No.14/550,618, filed Nov. 21, 2014, now U.S. Pat. No. 9,198,905; which is acontinuation-in-part of International Pat. App. No. PCT/US2014/064184,filed Nov. 5, 2014; which claims the benefit of U.S. Provisional Pat.App. No. 61/900,354, filed Nov. 5, 2013; any of the applications, U.S.patents issued from, or U.S. publications of any of the aboveapplications are incorporated by reference in their entirety.

SUMMARY

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being, comprising co-administering bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds with dextromethorphan.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being, comprising co-administeringerythrohydroxybupropion or a prodrug thereof, with dextromethorphan tothe human being, wherein the erythrohydroxybupropion or a prodrugthereof is administered in an amount that results in an AUC₀₋₁₂ ofdextromethorphan that is at least about 40 ng·hr/mL.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being, comprising co-administeringerythrohydroxybupropion or a prodrug thereof, with dextromethorphan tothe human being, wherein the erythrohydroxybupropion or a prodrugthereof is administered in an amount that results in a C_(max) ofdextromethorphan that is at least about 6 ng/mL.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being, comprising co-administeringerythrohydroxybupropion or a prodrug thereof, with dextromethorphan tothe human being, wherein the erythrohydroxybupropion or a prodrugthereof is administered in an amount that results in a C_(avg) ofdextromethorphan, over the period between two separate and consecutiveadministrations of dextromethorphan, that is at least about 5 ng/mL.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering threohydroxybupropion, ora prodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as threohydroxybupropion.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering threohydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with dextromethorphan.

Some embodiments include an oral sustained release delivery system fordextromethorphan, comprising bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any ofthese compounds, dextromethorphan, and a water soluble vehicle.

Some embodiments include a method of decreasing the number of doses ofdextromethorphan that can be administered without loss of efficacy,comprising orally administering an effective amount of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or aprodrug of any of these compounds, to a human being in need of treatmentwith dextromethorphan.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the threohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that threohydroxybupropion, or aprodrug thereof, and dextromethorphan are co-administered, as comparedto the same amount of dextromethorphan administered withoutthreohydroxybupropion or a prodrug thereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, isadministered on the first day of at least two days of treatment withdextromethorphan, wherein a decrease in the dextrorphan plasma leveloccurs on the first day that hydroxybupropion, or a prodrug thereof, anddextromethorphan are co-administered, as compared to the same amount ofdextromethorphan administered without hydroxybupropion or a prodrugthereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan to ahuman being in need of treatment with dextromethorphan, wherein thebupropion is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that bupropion and dextromethorphanare co-administered, as compared to the same amount of dextromethorphanadministered without bupropion.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the erythrohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that erythrohydroxybupropion, or aprodrug thereof, and dextromethorphan are co-administered, as comparedto the same amount of dextromethorphan administered withouterythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least eight consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the eighth day, the dextrorphanplasma level is lower than the dextrorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least nine consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the ninth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least nine consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the ninth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least nine consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the ninth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least nine consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theninth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for nine consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least ten consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the tenth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion for ten consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least ten consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thetenth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for ten consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least ten consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thetenth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for ten consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least ten consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thetenth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for ten consecutive days.

Antidepressant compounds, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, can be used to improve thetherapeutic properties, such as in the treatment of neurologicaldisorders, of dextromethorphan. Bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, regardless of stereochemistry, can beeffective in inhibiting or reducing the metabolism of dextromethorphanin some human beings. This may be accomplished by co-administeringbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan.

Some embodiments include a method of treating a neurological disordercomprising administering: 1) dextromethorphan, or 2) a combination of anantidepressant compound and dextromethorphan to a human being in needthereof, wherein the human being is an extensive metabolizer ofdextromethorphan.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering bupropion with dextromethorphan to the humanbeing.

Some embodiments include a method of inhibiting the metabolism ofdextromethorphan, comprising administering bupropion to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as bupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering bupropion to a human beingin need of treatment with dextromethorphan, wherein the human being isan extensive metabolizer of dextromethorphan, and whereindextromethorphan is present in the body of the human being at the sametime as bupropion.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering bupropion to a human being inneed thereof.

Some embodiments include a method of improving the antitussiveproperties of dextromethorphan comprising administering bupropion inconjunction with administration of dextromethorphan to a human being inneed of treatment for cough.

Some embodiments include a method of treating cough comprisingadministering a combination of bupropion or another active compound anddextromethorphan to a human being in need thereof.

Some embodiments include a method of treating a neurological disordercomprising administering 1) dextromethorphan, or 2) bupropion anddextromethorphan to a human being in need thereof, wherein the 1)dextromethorphan, or 2) bupropion and dextromethorphan are administeredat least once a day for at least 8 days, at least 9 days, or at least 10days.

Some embodiments include a method of treating a neurological disordercomprising administering about 150 mg/day to about 300 mg/day ofbupropion and about 15 mg/day to about 60 mg/day of dextromethorphan toa human being in need thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering hydroxybupropion, or a prodrug thereof, withdextromethorphan to the human being.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering erythrohydroxybupropion, or a prodrugthereof, with dextromethorphan to the human being.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering threohydroxybupropion, or a prodrug thereof,with dextromethorphan to the human being.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering bupropion to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as bupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time ashydroxybupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering erythrohydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time aserythrohydroxybupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering threohydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time asthreohydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as hydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering erythrohydroxybupropion,or a prodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as erythrohydroxybupropion.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan to ahuman being in need of treatment with dextromethorphan, wherein thebupropion is administered on the first day of at least two days ofco-administration of bupropion with dextromethorphan, wherein anincrease in the dextromethorphan plasma level occurs on the first daythat bupropion and dextromethorphan are co-administered, as compared tothe same amount of dextromethorphan administered without bupropion.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, isadministered on the first day of at least two days of co-administrationof hydroxybupropion, or a prodrug thereof, with dextromethorphan,wherein an increase in the dextromethorphan plasma level occurs on thefirst day that hydroxybupropion, or a prodrug thereof, anddextromethorphan are co-administered, as compared to the same amount ofdextromethorphan administered without hydroxybupropion or a prodrugthereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the erythrohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days ofco-administration of erythrohydroxybupropion, or a prodrug thereof, withdextromethorphan, wherein an increase in the dextromethorphan plasmalevel occurs on the first day that erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan are co-administered, as compared to thesame amount of dextromethorphan administered withouterythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the threohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days ofco-administration of threohydroxybupropion, or a prodrug thereof, withdextromethorphan, wherein an increase in the dextromethorphan plasmalevel occurs on the first day that threohydroxybupropion, or a prodrugthereof, and dextromethorphan are co-administered, as compared to thesame amount of dextromethorphan administered withoutthreohydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least five consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the fifth day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouthydroxybupropion, or a prodrug thereof, for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouterythrohydroxybupropion, or a prodrug thereof, for five consecutivedays.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutthreohydroxybupropion, or a prodrug thereof, for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least six consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the sixth day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouthydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouterythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutthreohydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering bupropion withdextromethorphan to a human patient in need of treatment withdextromethorphan, wherein dextromethorphan has a plasma level 12 hoursafter co-administering bupropion with dextromethorphan that is at leasttwice the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering hydroxybupropion, or aprodrug thereof, with dextromethorphan to a human patient in need oftreatment with dextromethorphan, wherein dextromethorphan has a plasmalevel 12 hours after co-administering hydroxybupropion, or a prodrugthereof, with dextromethorphan that is at least twice the plasma levelthat would be achieved by administering the same amount ofdextromethorphan without hydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering erythrohydroxybupropion,or a prodrug thereof, with dextromethorphan to a human patient in needof treatment with dextromethorphan, wherein dextromethorphan has aplasma level 12 hours after co-administering erythrohydroxybupropion, ora prodrug thereof, with dextromethorphan that is at least twice theplasma level that would be achieved by administering the same amount ofdextromethorphan without erythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering threohydroxybupropion, ora prodrug thereof, with dextromethorphan to a human patient in need oftreatment with dextromethorphan, wherein dextromethorphan has a plasmalevel 12 hours after co-administering threohydroxybupropion, or aprodrug thereof, with dextromethorphan that is at least twice the plasmalevel that would be achieved by administering the same amount ofdextromethorphan without threohydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering bupropion and dextromethorphan to a human patient inneed of dextromethorphan treatment, wherein the human patient is at riskof experiencing the adverse event as a result of being treated withdextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering hydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering erythrohydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by bupropion, comprising co-administeringdextromethorphan and bupropion to a human patient in need of bupropiontreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with bupropion.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering erythrohydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering threohydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering bupropion in conjunction withadministration of dextromethorphan to a human being in need of treatmentfor cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering hydroxybupropion, or a prodrugthereof, in conjunction with administration of dextromethorphan to ahuman being in need of treatment for cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering erythrohydroxybupropion, or aprodrug thereof, in conjunction with administration of dextromethorphanto a human being in need of treatment for cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering threohydroxybupropion, or aprodrug thereof, in conjunction with administration of dextromethorphanto a human being in need of treatment for cough.

Some embodiments include a method of treating cough comprisingadministering a combination of hydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating cough comprisingadministering a combination of erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating cough comprisingadministering a combination of threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating a neurological disordercomprising administering bupropion and dextromethorphan to a human beingin need thereof, wherein the bupropion and dextromethorphan areadministered at least once a day for at least 8 days, at least 9 days,or at least 10 days.

Some embodiments include a method of treating a neurological disordercomprising administering hydroxybupropion, or a prodrug thereof, anddextromethorphan to a human being in need thereof, wherein the bupropionand dextromethorphan are administered at least once a day for at least 8days, at least 9 days, or at least 10 days.

Some embodiments include a method of treating a neurological disordercomprising administering erythrohydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof, wherein theerythrohydroxybupropion and dextromethorphan are administered at leastonce a day for at least 8 days, at least 9 days, or at least 10 days.

Some embodiments include a method of treating a neurological disordercomprising administering threohydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof, wherein thethreohydroxybupropion and dextromethorphan are administered at leastonce a day for at least 8 days, at least 9 days, or at least 10 days.

Some embodiments include a pharmaceutical composition, dosage form, ormedicament comprising a therapeutically effective amount ofdextromethorphan, a therapeutically effective amount of anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, and a pharmaceutically acceptableexcipient.

Some embodiments include a method of reducing a risk of seizureassociated with use of bupropion to treat depression, comprising orallyadministering a dextromethorphan-bupropion combination twice a day,wherein the method is: 1) at least as effective in treating depression,and 2) reduces the risk of seizure to the human being, as compared toorally administering 150 mg of the bupropion alone twice a day to thehuman being for the same number of days.

Some embodiments include a method of improving the therapeutic effect ofbupropion in treating depression, comprising orally co-administering adextromethorphan with a bupropion, twice a day, to a human beingsuffering from depression, wherein the method is more effective thantreating the depression of that human being by orally administering 150mg of the bupropion alone twice a day to the human being for five weeks.

In some embodiments, the combination of the dextromethorphan and thebupropion is more effective than independently orally administering thesame amount of the dextromethorphan or the bupropion alone.

Some embodiments include a method of improving the efficacy of bupropionin treating depression, comprising orally administering about 90 mg toabout 125 mg of a bupropion in combination with about 0.3 mg/kg to about1 mg/kg of a dextromethorphan, once or twice a day for at least 23 days,to a human being suffering from depression, wherein orally administeringthe bupropion in combination with the dextromethorphan is more effectivein treating depression than orally administering the same dosage regimenof bupropion without dextromethorphan.

Some embodiments include a method of treating treatment-resistantdepression comprising: selecting a human being suffering from depressionwho has previously been unsuccessfully treated with at least oneantidepressant; and orally administering a dextromethorphan-bupropioncombination treatment once or twice a day to the human being for atleast about five weeks; wherein the dextromethorphan-bupropioncombination treatment comprises about 40 mg to about 70 mg of adextromethorphan and about 100 mg to about 140 mg of a bupropion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the mean plasma concentrations of dextromethorphanover time after dosing on Day 8 for subjects administereddextromethorphan alone or dextromethorphan and bupropion.

FIG. 2 depicts mean AUC₀₋₁₂ of dextromethorphan on Day 8 for subjectsadministered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 3 depicts mean AUC₀₋₂₄ of dextromethorphan on Day 8 for subjectsadministered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 4 depicts mean AUC_(0-inf) of dextromethorphan on Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 5 depicts the fold changes in AUCs of dextromethorphan on Day 8 forsubjects administered dextromethorphan alone as compared todextromethorphan and bupropion.

FIG. 6 depicts mean AUC₀₋₁₂ of dextromethorphan on Day 1 and Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 7 depicts mean dextromethorphan trough plasma concentrations forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 8 depicts mean dextromethorphan maximum plasma concentrations onDay 1 and Day 8 for subjects administered dextromethorphan alone ordextromethorphan and bupropion.

FIG. 9 is a plot of the mean plasma concentrations of dextrorphan overtime after dosing on Day 8 for subjects administered dextromethorphanalone or dextromethorphan and bupropion.

FIG. 10 depicts mean dextrorphan maximum plasma concentrations on Day 1and Day 8 for subjects administered dextromethorphan alone ordextromethorphan and bupropion.

FIG. 11 depicts mean AUC₀₋₁₂ of dextrorphan on Day 1 and Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 12 depicts the potency of various antidepressant compounds forinhibition of the metabolism of dextromethorphan in human livermicrosomes.

FIG. 13 is a plot of the average MADRS total score change from baselineover time during the 6-week dosing period for subjects administeredbupropion alone or the combination of dextromethorphan and bupropion.

FIG. 14 depicts the percent of subjects achieving remission (MADRS≤10)over time during the 6-week dosing period for subjects administeredbupropion alone or the combination of dextromethorphan and bupropion.

DETAILED DESCRIPTION

Some embodiments include a method of treating neurological disorderscomprising administering a therapeutically effective amount ofdextromethorphan and a therapeutically effective amount of anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, to a person in need thereof.

Some embodiments include a method of enhancing the therapeuticproperties of dextromethorphan in treating neurological disorders,comprising co-administering dextromethorphan and an antidepressant, suchas bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being that is an extensive metabolizer ofdextromethorphan, comprising co-administering an antidepressantcompound, such as bupropion, and dextromethorphan to the human being.

Some embodiments include a method of inhibiting the metabolism ofdextromethorphan, comprising administering an antidepressant compound,such as bupropion, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time as theantidepressant.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, including increasing the elimination half-life(T_(1/2)) of dextromethorphan. These embodiments may compriseadministering an antidepressant compound, such as bupropion, to a humanbeing, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as the antidepressant compound.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering an antidepressant compound,such as bupropion, to a human being in need thereof, such as a humanbeing in need of treatment for pain.

Some embodiments include a method of improving the therapeuticproperties of dextromethorphan in treating neurological disorderscomprising administering an antidepressant compound, such as bupropion,in conjunction with administration of dextromethorphan to a human beingin need of treatment for a neurological disorder.

Some embodiments include a method of treating neurological disorderscomprising administering a combination of an antidepressant compound,such as bupropion, and dextromethorphan to a human being in needthereof.

Co-administration of an antidepressant compound, such as bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or aprodrug of the antidepressant compound, with dextromethorphan may occurone or more times for a single day, or for 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or more consecutive days.In some embodiments, co-ad ministration is at least daily for at leasttwo consecutive days.

In some embodiments, co-administration of an antidepressant compound,such as bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a prodrug of the antidepressant compound,with dextromethorphan may occur once a day for 1, 2, 3, 4, 5, 6, or 7days, prior to co-administration twice a day.

Dextromethorphan has the structure shown below.

Dextromethorphan is used as a cough suppressant. According to the FDA'sdextromethorphan product labeling requirement under the OTC Monograph[21CFR341.74], dextromethorphan should be dosed 6 times a day (every 4hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).

Dextromethorphan is rapidly metabolized in the human liver. This rapidhepatic metabolism may limit systemic drug exposure in individuals whoare extensive metabolizers. Human beings can be: 1) extensivemetabolizers of dextromethorphan—those who rapidly metabolizedextromethorphan; 2) poor metabolizers of dextromethorphan—those whoonly poorly metabolize dextromethorphan; or 3) intermediate metabolizersof dextromethorphan—those whose metabolism of dextromethorphan issomewhere between that of an extensive metabolizer and a poormetabolizer. Extensive metabolizers can also be ultra-rapidmetabolizers. Extensive metabolizers of dextromethorphan are asignificant portion of the human population. Dextromethorphan can, forexample, be metabolized to dextrorphan.

When given the same oral dose of dextromethorphan, plasma levels ofdextromethorphan are significantly higher in poor metabolizers orintermediate metabolizers as compared to extensive metabolizers ofdextromethorphan. The low plasma concentrations of dextromethorphan canlimit its clinical utility as a single agent for extensive metabolizers,and possibly intermediate metabolizers, of dextromethorphan. Sometherapeutically active compounds, including antidepressants such asbupropion, inhibit the metabolism of dextromethorphan, and raise theplasma concentration of dextromethorphan, and can thus improve itstherapeutic efficacy. Similarly, antidepressants may allowdextromethorphan to be given less often, such as once a day instead oftwice a day, once a day instead of three times a day, once a day insteadof four times a day, twice a day instead of three times a day, or twicea day instead of four times a day, without loss of therapeutic efficacy.

Co-administration of an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, with dextromethorphanor dextrorphan may enhance the mechanisms of action, or pharmacologicalproperties of dextromethorphan and dextrorphan. Mechanisms of action ofdextromethorphan and dextrorphan can include sigma-1 agonist and NMDAantagonist properties, calcium channel blockade, muscarinic binding,serotonin transporter (5HTT) inhibition, and mu receptor potentiation.

Some embodiments include co-administration of an antidepressant such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, with dextromethorphan or dextrorphan to agonize, antagonize,or modulate a sigma-1 receptor, or an NMDA receptor; to block a calciumchannel; to bind to a muscarinic receptor; to inhibit a serotonintransporter (5HTT); or to potentiate a mu receptor.

Pharmacological properties of dextromethorphan and dextrorphan caninclude NMDA high-affinity site, NMDR-2A, and functional NMDR-2Breceptor antagonism, sigma-1 stimulation, putative mTOR activation (bysigma-1 stimulation, mu potentiation, beta adrenoreceptor stimulation,and 5HTT inhibition), putative AMPA receptor trafficking (by mTORactivation, PCP antagonism, sigma-1 stimulation, beta stimulation, mupotentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis,synaptogenesis, and neuronal survival by NMDA antagonism and sigma-1 andmTOR signaling. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto bind to, agonize, antagonize, stimulate, activate, inhibit, influencethe trafficking of, or modulate an NMDA high-affinity site, NMDR-2A, afunctional NMDR-2B receptor, sigma-1 receptor, a putative mTOR receptor(such as by stimulating sigma-1, potentiating a mu receptor, stimulatinga beta adrenoreceptor, or inhibiting a 5HTT), or a putative AMPAreceptor (such as by activating mTOR, antagonizing PCP activity,stimulating a sigma-1 receptor, stimulating a beta adrenergic receptor,potentiating a mu receptor, or inhibiting 5HTT). Some embodimentsinclude co-administration of an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, with dextromethorphanor dextrorphan to cause, increase, decrease, or otherwise modulatedendritogenesis, spinogenesis, or synaptogenesis. Some embodimentsinclude co-administration of an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, with dextromethorphanor dextrorphan to cause, increase, decrease, or otherwise modulateneuronal survival by NMDA antagonism and/or sigma-1 and/or mTORsignaling.

Pharmacological properties of dextromethorphan and dextrorphan caninclude 5HTT and norepinephrine transporter inhibition, sigma-1stimulation, NMDA and PCP antagonism, and possible serotonin 5HT1b/dreceptor stimulation. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto bind to, agonize, antagonize, stimulate, activate, inhibit, influencethe trafficking of, or modulate the 5HTT and/or norepinephrinetransporter, the sigma-1 receptor, NMDA and/or PCP receptor, and/or tostimulate the serotonin 5HT1b/d receptor.

Additional properties for dextromethorphan and dextrorphan can includepossible presynaptic alpha-2 adrenoreceptor antagonism or postsynapticalpha-2 stimulation, beta stimulation and possible muscarinic and muantagonism. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto bind to, agonize, antagonize, stimulate, activate, inhibit, influencethe trafficking of, or modulate a presynaptic alpha-2 adrenoreceptor,postsynaptic alpha-2 receptor, beta adrenoreceptor, muscarinic receptor,or mu receptor. Dextromethorphan and dextrorphan may be glial cellmodulators. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto modulate glial cells.

Pain or other neurological disorders may be treated by enhancingdextromethorphan plasma levels or increasing dextromethorphanbioavailability, for example by a method comprising administering atherapeutically effective amount of dextromethorphan and atherapeutically effective amount of an antidepressant compound, such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, to a person in need thereof.

Examples of neurological disorders that may be treated, or that may betreated with increased efficacy, by enhanced dextromethorphan levels,such as those achievable by a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, include, but are not limited to:affective disorders, psychiatric disorders, cerebral function disorders,movement disorders, dementias, motor neuron diseases, neurodegenerativediseases, seizure disorders, and headaches.

Affective disorders that may be treated by enhanced dextromethorphanlevels or by a combination of dextromethorphan and an antidepressantsuch as bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, include, but are not limited to, depression, majordepression, treatment resistant depression and treatment resistantbipolar depression, bipolar disorders including cyclothymia, seasonalaffective disorder, mood disorders, chronic depression (dysthymia),psychotic depression, postpartum depression, premenstrual dysphoricdisorder (PMDD), situational depression, atypical depression, mania,anxiety disorders, attention deficit disorder (ADD), attention deficitdisorder with hyperactivity (ADDH), and attention deficit/hyperactivitydisorder (AD/HD), bipolar and manic conditions, obsessive-compulsivedisorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatiguesyndrome, premenstrual syndrome, substance addiction or abuse, nicotineaddiction, psycho-sexual dysfunction, pseudobulbar affect, and emotionallability.

Depression may be manifested by depressive symptoms. These symptoms mayinclude psychological changes such as changes in mood, feelings ofintense sadness, despair, mental slowing, loss of concentration,pessimistic worry, agitation, anxiety, irritability, guilt, anger,feelings of worthlessness, reckless behavior, suicidal thoughts orattempts, and/or self-deprecation. Physical symptoms of depression mayinclude insomnia, anorexia, appetite loss, weight loss, weight gain,decreased energy and libido, fatigue, restlessness, aches, pains,headaches, cramps, digestive issues, and/or abnormal hormonal circadianrhythms.

Some patients, even after treatment with medications such asantidepressants, may have an inadequate or no response to the treatment.Treatment resistant depression (TRD), or treatment-refractorydepression, is a condition generally associated with patients who havefailed treatment with at least two antidepressants. Part of thediagnosis for TRD is for the patient to have had an inadequate responseto treatment with the antidepressants after an adequate dose andadequate course. TRD may be more difficult to treat due to thecomorbidity of other medical or psychological illnesses, such asdrug/alcohol abuse or eating disorders, or TRD being misdiagnosed. SomeTRD patients have had an inadequate response to 1, 2, 3, or moreadequate antidepressant treatment trials or have failed or had aninadequate response to 1, 2, 3, or more prior antidepressant treatments.In some embodiments, a patient being treated for treatment resistantdepression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, or more antidepressant therapies.

Measures of treatment effect that may be improved by treatment withenhanced bioavailability or plasma levels of dextromethorphan, or by acombination of dextromethorphan and an antidepressant, such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, include, but are not limited to: Montgomery-Asberg DepressionRating Scale (MADRS), Quality of Life Enjoyment and SatisfactionQuestionnaire Short Form, Range of Impaired Functioning Tool, SheehanDisability Scale, Patient Rated Inventory of Side Effects (PRISE),Columbia-Suicide Severity Rating Scale (C-SSRS), Quick Inventory ofDepressive Symptomatology, Self-Report (QIDS-SR), Clinical GlobalImpression (CGI) scale, Massachusetts General Hospital Cognitive andPhysical Functioning Questionnaire (CPFQ), 17-item Hamilton Rating Scalefor Depression (HAM-D17), Massachusetts General Hospital AntidepressantTreatment Response Questionnaire (MGH ATRQ), 16-item Quick Inventory ofDepressive Symptomatology-Self Report (QIDS-SR16), Sheehan DisabilityScale (SDS), Clinical Global Impression of Severity of Illness (CGI-S),Clinical Global Impression of Change (CGI-C), EuroQOL 5 Dimension 5Level (EQ-5D-5L), Patient Global Impression of Change (PGIC), 7-itemGeneralized Anxiety Disorder (GAD-7), Clinical GlobalImpressions-Improvement (CGI-I). Sheehan Disability Scale (SDS). 16-itemQuick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16),Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitiveand Physical Functioning Questionnaire (CPFQ), CPFQ—Cognitive subscales(Items 4 to 7), Brief Psychiatric Rating Scale (BPRS), etc.; DigitSymbol Substitution Test (DSST), Rey Auditory Verbal Learning Task(RAVLT), Trail Making Test (TMT), Stroop Colour Naming Test (STROOP),Simple Reaction Time (SRT), Choice Reaction Time (CRT). etc.

In some embodiments, an enhanced bioavailability of dextromethorphan, ora combination of dextromethorphan and an antidepressant such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, may have an onset of action within 30 minutes, 1 hour, 2hours, 3 hours, 4 hours, 5 hours, 6 hours, 6-8 hours, 8-12 hours, 12hours, a day, 1-7 days, 1 week, two weeks, three weeks, four weeks, sixweeks, or eight weeks.

Patients who may benefit from the treatments described herein includepediatric patients, such as patients under about 18 years of age, about0-5 years of age, about 5-10 years of age, about 10-12 years of age, orabout 12-18 years of age; adult patients, such as patients having an ageof about 18-65 years, about 18-30 years, about 30-50 years, about 50-65years; and elderly patients, such as patients over 65 years of age,about 65-75 years of age, about 75-90 years of age, or over 90 years ofage.

In some embodiments, an enhanced bioavailability of dextromethorphan, ora combination of dextromethorphan and an antidepressant such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, may be used as an adjunctive therapy for treatment of anycondition recited herein, including TRD. For example, the adjunctivetherapy could be used in combination with another antidepressant, suchas bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin,imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine,protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine,isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram,sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine,venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone,selegiline, sibutramine, milnacipran, tesofensine, brasofensine,moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone,butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol,norfluoxetine, dapoxetine, ketamine, etc., or a metabolite or prodrug ofany of these compounds, or a pharmaceutically acceptable salt of any ofthese compounds.

In some embodiments, TRD may be treated by enhanced bioavailability orplasma levels of dextromethorphan, or by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds and may result in areduction of depressive symptoms of at least about 5%, at least about10%, at least about 20%, at least about 30%, at least about 40%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, up to about 100%, or any other reduction in arange bounded by any of these values.

Psychiatric disorders that may be treated by enhanced plasma levels ofdextromethorphan such as those achieved by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, include, but are notlimited to, anxiety disorders, including but not limited to, phobias,generalized anxiety disorder, social anxiety disorder, panic disorder,agoraphobia, obsessive-compulsive disorder, and post-traumatic stressdisorder (PTSD); mania, manic depressive illness, hypomania, unipolardepression, depression, stress disorders, somatoform disorders,personality disorders, psychosis, schizophrenia, delusional disorder,schizoaffective disorder, schizotypy, aggression, aggression inAlzheimer's disease, agitation, and agitation in Alzheimer's disease.

Agitation in Alzheimer's disease occurs as the disease progresses.Agitation may present itself as inappropriate verbal, emotional, and/orphysical behaviors. Inappropriate behaviors may include, but are notlimited to, incoherent babbling, inappropriate emotional response,demands for attention, threats, irritability, frustration, screaming,repetitive questions, mood swings, cursing, abusive language, physicaloutbursts, emotional distress, restlessness, shredding, sleepingdisturbances, delusions, hallucinations, pacing, wandering, searching,rummaging, repetitive body motions, hoarding, shadowing, hitting,scratching, biting, combativeness, hyperactivity, and/or kicking.

In some embodiments, agitation in Alzheimer's disease may be treated byenhanced plasma levels of dextromethorphan or by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds and may result in areduction of agitation-related symptoms of at least about 5%, at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, up to about 100%, or any other reductionin a range bounded by any of these values.

Measures of treatment effect that may be improved by treatment withenhanced bioavailability or plasma levels of dextromethorphan, or by acombination of dextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, Neuropsychiatric Inventory-Clinician (NPI-C) rating scale,overall and all domains; Neuropsychiatric Inventory-Clinician (NPI-C)rating scale Agitation domain; Cohen-Mansfield Agitation Inventory(CMAI); Cornell Scale for Depression in Dementia (CSDD);Neuropsychiatric Inventory (NPI Agitation/Aggression Domain); CocomitantMedications (Frequency of using concomitant medications); Alzheimer'sDisease Cooperative Study-Activities of Daily Living Inventory(ADCS-ADL); Neuropsychiatric Inventory (NPI) Individual Domains and NPITotal Scores (range 0-144), including NPI-C Apathy domain, NPIAgitation/Aggression Caregiver Distress, Modified Alzheimer's DiseaseCooperative Study-Clinical Global Impression of Change Agitation(mADCS-CGIC Agitation), Patient Global Impression of Change (PGIC)(rated by caregiver), Dementia Quality of Life (DEMQOL), Quality ofLife-Alzheimer's disease measure (QoL-AD), Zarit Burden Scale, ResourceUtilization in Dementia (RUD), Alzheimer's Disease AssessmentScale-Cognitive Subscale (ADAS-Cog), Mini-mental State Examination(MMSE), Caregiver Strain Index (CSI), Individual Domain of theNeuropsychiatric Inventory (NPI), Total Neuropsychiatric Inventory (NPI)Score, Neuropsychiatric Inventory (Agitation/Aggression Domain of NPI),Neuropsychiatric Inventory (Caregiver Distress for NPI Domains), etc.

Substance addiction abuse that may be treated by enhancedbioavailability or plasma levels of dextromethorphan or by a combinationof dextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, includes, but is notlimited to, drug dependence, addiction to cocaine, psychostimulants(e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids,anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines,hallucinogens, phencyclidine, volatile solvents, and volatile nitrites.Nicotine addiction includes nicotine addiction of all known forms, suchas smoking cigarettes, cigars and/or pipes, and addiction to chewingtobacco.

Cerebral function disorders that may be treated by enhancedbioavailability or plasma levels of dextromethorphan, or by acombination of dextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, disorders involving intellectual deficits such as seniledementia, Alzheimer's type dementia, memory loss, amnesia/amnesticsyndrome, epilepsy, disturbances of consciousness, coma, lowering ofattention, speech disorders, voice spasms, Parkinson's disease,Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, andschizophrenia. Cerebral function disorders also include disorders causedby cerebrovascular diseases including, but not limited to, stroke,cerebral infarction, cerebral bleeding, cerebral arteriosclerosis,cerebral venous thrombosis, head injuries, and the like where symptomsinclude disturbance of consciousness, senile dementia, coma, lowering ofattention, and speech disorders.

Movement disorders that may be treated by enhanced bioavailability orplasma levels of dextromethorphan, or by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, akathisia, akinesia, associated movements, athetosis,ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea,Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia,tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis,dopamine-responsive dystonia, Parkinson's disease, restless legssyndrome (RLS), tremor, essential tremor, and Tourette's syndrome, andWilson's disease.

Dementias that may be treated by enhanced bioavailability or plasmalevels of dextromethorphan, or by a combination of dextromethorphan andan antidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds include, but are not limited to,Alzheimer's disease, Parkinson's disease, vascular dementia, dementiawith Lewy bodies, mixed dementia, fronto-temporal dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington'sdisease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by enhanced bioavailability orplasma levels of dextromethorphan, or by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, amyotrophic lateral sclerosis (ALS), progressive bulbarpalsy, primary lateral sclerosis (PLS), progressive muscular atrophy,post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motoratrophies, Tay-Sach's disease, Sandoff disease, and hereditary spasticparaplegia.

Neurodegenerative diseases that may be treated by enhancedbioavailability or plasma levels of dextromethorphan, or by acombination of dextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, Alzheimer's disease, prion-related diseases, cerebellarataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA),bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewybody disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS orLou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy,Shy-Drager syndrome, corticobasal degeneration, progressive supranuclearpalsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebralautosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Toothdisease (CMT), familial spastic paraparesis, neurofibromatosis,olivopontine cerebellar atrophy or degeneration, striatonigraldegeneration, Guillain-Barré syndrome, and spastic paraplesia.

Seizure disorders that may be treated by enhanced bioavailability orplasma levels of dextromethorphan, or by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, epileptic seizures, nonepileptic seizures, epilepsy, febrileseizures; partial seizures including, but not limited to, simple partialseizures, Jacksonian seizures, complex partial seizures, and epilepsiapartialis continua; generalized seizures including, but not limited to,generalized tonic-clonic seizures, absence seizures, atonic seizures,myoclonic seizures, juvenile myoclonic seizures, and infantile spasms;and status epilepticus.

Types of headaches that may be treated by enhanced bioavailability orplasma levels of dextromethorphan, or by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, migraine, tension, and cluster headaches.

Other neurological disorders that may be treated by enhancedbioavailability or plasma levels of dextromethorphan, or by acombination of dextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, Rett Syndrome,autism, tinnitus, disturbances of consciousness disorders, sexualdysfunction, intractable coughing, narcolepsy, cataplexy; voicedisorders due to uncontrolled laryngeal muscle spasms, including, butnot limited to, abductor spasmodic dysphonia, adductor spasmodicdysphonia, muscular tension dysphonia, and vocal tremor; diabeticneuropathy, chemotherapy-induced neurotoxicity, such as methotrexateneurotoxicity; incontinence including, but not limited, stress urinaryincontinence, urge urinary incontinence, and fecal incontinence; anderectile dysfunction.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may be used to treat pain, jointpain, pain associated with sickle cell disease, pseudobulbar affect,depression (including treatment resistant depression), disorders relatedto memory and cognition, schizophrenia, Parkinson's disease, amyotrophiclateral sclerosis (ALS), Rhett's syndrome, seizures, cough (includingchronic cough), etc.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat treatmentrefractory depression.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat allodynia.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat treatmentrefractory hyperalgesia.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat dermatitis.

Pain relieving properties of dextromethorphan may be enhanced by amethod comprising co-administering dextromethorphan and anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan.

Pain relieving properties of bupropion may be enhanced by a methodcomprising co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, ketamine or another NMDA receptor antagonist may beadministered with an antidepressant, such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, dextromethorphan and quinidine may beco-administered with an antidepressant, such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

These methods may be used to treat, or provide relief to, any type ofpain including, but not limited to, musculoskeletal pain, neuropathicpain, cancer-related pain, acute pain, nociceptive pain, inflammatorypain, arthritis pain, complex regional pain syndrome, etc.

In some embodiments, co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be used to treat orreduce inflammation or inflammatory conditions, such as Crohn's disease,including pain associated with inflammation.

In some embodiments, co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be used to treatpsoriasis, cancer, viral infection, or as an adjuvant treatment formultiple myeloma.

Examples of musculoskeletal pain include low back pain (i.e. lumbosacralpain), primary dysnnenorrhea, and arthritic pain, such as painassociated with rheumatoid arthritis, juvenile rheumatoid arthritis,osteoarthritis, axial spondyloarthritis including ankylosingspondylitis, pain associated with vertebral crush fractures, fibrousdysplasia, osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered orally to relievemusculoskeletal pain including low back pain, and pain associated withrheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, axialspondyloarthritis including ankylosing spondylitis, Paget's disease,fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip,vertebral crush fractures, osteoporosis, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered to relieveinflammatory pain including musculoskeletal pain, arthritis pain, andcomplex regional pain syndrome.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include pain associated withosteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, is used to treat chronicmusculoskeletal pain.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered to relievecomplex regional pain syndrome, such as complex regional pain syndrometype I (CRPS-I), complex regional pain syndrome type II (CRPS-II),CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain.CRPS can also have a neuropathic component. Complex regional painsyndrome is a debilitating pain syndrome. It is characterized by severepain in a limb that can be accompanied by edema, and autonomic, motorand sensory changes.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered orally to relieveneuropathic pain.

Examples of neuropathic pain include diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, central pain, etc. Other causes of neuropathic paininclude cancer-related pain, lumbar nerve root compression, spinal cordinjury, post-stroke pain, central multiple sclerosis pain,HIV-associated neuropathy, and radio- or chemo-therapy associatedneuropathy, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered to relievefibromyalgia.

The term “treating”, or “treatment” includes the diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals,or any activity that otherwise affects the structure or any function ofthe body of man or other animals.

Any antidepressant may be used in combination with dextromethorphan toimprove the therapeutic properties of dextromethorphan. Dextromethorphanand the antidepressant compound may be administered in separatecompositions or dosage forms or may be administered in a singlecomposition or dosage form comprising both.

A quinidine may be co-administered with dextromethorphan to provideenhanced plasma levels of dextromethorphan. For a combination of aquinidine and a dextromethorphan (including deuterium-modifieddextromethorphan, e.g. d6-dextromethorphan, and non-deuterium modifieddextromethorphan), a daily dose of about 1-1,000 mg, 1-10 mg, 10 mg,about 5 mg, about 4.5, about 1-3 mg, about 2-4 mg, about 3-5 mg, about4-6 mg, about 5-7 mg, about 6-8 mg, about 7-9 mg, about 8-10 mg, about9-11 mg, about 10-12 mg, about 4.5-5 mg, 20 mg, 30 mg, 30-100 mg, about40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 10-30 mg, about 30-50 mg, about 50-70 mg, about 10-90 mg of thequinidine, or any dose in a range bounded by any of these values.

Antidepressant compounds that can be co-administered withdextromethorphan include, but are not limited to, bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion,clomipramine, doxepin, fluoxetine, mianserin, imipramine,2-chloroimipramine, amitriptyline, amoxapine, desipramine,protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine,isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram,sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine,venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone,selegiline, sibutramine, milnacipran, tesofensine, brasofensine,moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone,butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol,norfluoxetine, dapoxetine, ketamine, etc., or a metabolite or prodrug ofany of these compounds, or a pharmaceutically acceptable salt of any ofthese compounds.

For a combination of a ketamine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.01-0.2mg, about 0.2-0.4 mg, about 0.4-0.6 mg, about 0.6-0.8 mg, about 0.8-1mg, about 1-1.2 mg, about 1.2-1.4 mg, about 1.4-1.6 mg, about 1.6-1.8mg, about 1.8-2 mg, about 2-2.2 mg, about 2.2-2.4 mg, about 2.4-2.6 mg,about 2.6-2.8 mg, about 2.8-3 mg, about 3-3.2 mg, about 3.2-3.4 mg,about 3.4-3.6 mg, about 3.6-3.8 mg, about 3.8-4 mg, about 3.9-4.1 mg,about 4-4.2 mg, about 0.2-0.4 mg, about 0.2-0.6 mg, about 0.2-0.8 mg,about 0.2-1 mg, about 0.2-1.2 mg, about 0.2-1.4 mg, about 0.2-1.6 mg,about 0.2-1.8 mg, about 0.2-2.0 mg, 0.2-2.5 mg, about 0.2-3.0 mg, about0.2-3.5 mg, about 0.2-4.0 mg, about 5-10 mg, about 10-15 mg, about 15-20mg, about 20-25 mg, about 25-30 mg, about 30-40 mg, about 40-50 mg,about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about90-100 mg, about 100-120 mg, about 120-140 mg, about 140-150 mg, about150-160 mg, about 160-180 mg, about 180-200 mg, about 200-220 mg, about220-240, about 10-500 mg, about 50-400 mg, about 50-300 mg, about100-250 mg, about 1-10 mg, about 10-200 mg, about 10-150 mg, about10-100 mg, about 10-180 mg, about 10-160 mg, about 10-140 mg, about10-120 mg, about 10-100 mg, about 10-20 mg, about 20-30 mg, about 30-40mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg,about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg,about 140-160 mg, about 160-180 mg, about 180-200 mg, about 200-220 mg,about 220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg,about 280-300 mg, about 300-350 mg, about 350-400 mg, about 25 mg, about50 mg, about 100 mg, about 250 mg, of the ketamine, or any dose in arange bounded by any of these values, may be administered.

For a combination of a tesofensine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.2mg, about 0.1-0.3 mg, about 0.1-0.4 mg, about 0.1-0.5 mg, about 0.1-0.6mg, about 0.1-0.7 mg, about 0.1-0.8 mg, about 0.1-0.9 mg, about 0.1-0.1mg, about 0.1-0.12 mg, 0.01-0.2 mg, about 0.1-0.3 mg, about 0.2-0.4 mg,about 0.3-0.5 mg, about 0.4-0.6 mg, about 0.5-0.7 mg, about 0.6-0.8 mg,about 0.7-0.9 mg, about 0.8-1 mg, about 0.9-1.1 mg, of the tesofensine,or any dose in a range bounded by any of these values, may beadministered.

For a combination of a brasofensine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.01-0.2mg, about 0.2-0.4 mg, about 0.4-0.6 mg, about 0.6-0.8 mg, about 0.8-1mg, about 1-1.2 mg, about 1.2-1.4 mg, about 1.4-1.6 mg, about 1.6-1.8mg, about 1.8-2 mg, about 2-2.2 mg, about 2.2-2.4 mg, about 2.4-2.6 mg,about 2.6-2.8 mg, about 2.8-3 mg, about 3-3.2 mg, about 3.2-3.4 mg,about 3.4-3.6 mg, about 3.6-3.8 mg, about 3.8-4 mg, about 3.9-4.1 mg,about 4-4.2 mg, about 0.2-0.4 mg, about 0.2-0.6 mg, about 0.2-0.8 mg,about 0.2-1 mg, about 0.2-1.2 mg, about 0.2-1.4 mg, about 0.2-1.6 mg,about 0.2-1.8 mg, about 0.2-2.0 mg, 0.2-2.5 mg, about 0.2-3.0 mg, about0.2-3.5 mg, about 0.2-4.0 mg, of the brasofensine, or any dose in arange bounded by any of these values, may be administered.

For a combination of a clomipramine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 10-500mg, about 50-400 mg, about 50-300 mg, about 100-250 mg, about 1-10 mg,about 10-200 mg, about 10-150 mg, about 10-100 mg, about 10-180 mg,about 10-160 mg, about 10-140 mg, about 10-120 mg, about 10-100 mg,about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180mg, about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-350 mg,about 350-400 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg,of the clomipramine, or any dose in a range bounded by any of thesevalues, may be administered.

For a combination of a doxepin and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-500mg, about 1-10 mg, about 1-40 mg, about 1-30 mg, about 1-20 mg, about1-18 mg, about 1-16 mg, about 1-14 mg, about 1-12 mg, about 1-10 mg,about 10-150 mg, about 10-125 mg, about 10-100 mg, about 10-75 mg, about10-70 mg, about 10-60 mg, about 10-50 mg, about 10-40 mg, about 10-30mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg,about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg, about160-180 mg, about 180-200 mg, about 200-220 mg, about 220-240, about240-250 mg, about 250-260 mg, about 260-280 mg, about 280-300 mg, about300-320 mg, about 320-350 mg, about 350-400 mg, about 400-500 mg, about25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250mg, about 300 mg, of the doxepin, or any dose in a range bounded by anyof these values, may be administered.

For a combination of a fluoxetine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of a daily doseof about 1-10 mg, about 5-15 mg, about 10-20 mg, about 20-30 mg, about30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg,about 140-160 mg, about 160-180 mg, about 180-200 mg, about 10 mg, about20 mg, about 60 mg, about 100 mg, about 150 mg, of the fluoxetine, orany dose in a range bounded by any of these values, may be administered.

For a combination of a mianserin and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-300mg, about 1-90 mg, about 1-60 mg, about 1-30 mg, about 1-25 mg, about1-20 mg, about 1-15 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg,about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg, about30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, of themianserin, or any dose in a range bounded by any of these values, may beadministered.

For a combination of a imipramine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 5-150 mg, about 5-125 mg, about 5-100 mg, about 5-75 mg, about5-60 mg, about 5-50 mg, about 5-40 mg, about 5-30 mg, about 5-25 mg,about 5-20 mg, about 5-15 mg, about 10-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200 mg,about 200-220 mg, about 220-240, about 240-250 mg, about 250-260 mg,about 260-280 mg, about 280-300 mg, about 300-320 mg, about 320-350 mg,about 350-400 mg, about 400-500 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, of theimipramine, or any dose in a range bounded by any of these values, maybe administered.

For a combination of a 2-chloroimipramine and a dextromethorphan(including deuterium-modified dextromethorphan, e.g.d6-dextromethorphan, and non-deuterium modified dextromethorphan), adaily dose of about 0.1-0.25 mg, about 0.25-0.5 mg, about 0.5-0.75 mg,about 0.75-1 mg, about 1-5 mg, about 5-10 mg, about 10-15 mg, about15-20 mg, about 20-25 mg, about 25-30 mg, about 30-40 mg, about 40-50mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg,about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-150 mg,about 150-160 mg, about 160-180 mg, about 180-200 mg, about 200-220 mg,about 220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg,about 280-300 mg, about 300-320 mg, about 320-350 mg, about 350-400 mg,about 400-450 mg, about 450-500 mg, about 500-550 mg, about 550-600 mg,about 600-650 mg, about 650-700 mg, about 700-800 mg, about 800-1000 mg,about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about250 mg, about 300 mg, about 400 mg, about 600 mg, of the about2-chloroimipramine, or any dose in a range bounded by any of thesevalues, may be administered.

For a combination of an amitriptyline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 5-100 mg, about 5-70 mg, about 5-60 mg, about 5-50 mg, about 5-40mg, about 5-35 mg, about 5-30 mg, about 5-25 mg, about 5-20 mg, about10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg,about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-500 mg, about 10 mg, about25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250mg, about 300 mg, of the amitriptyline, or any dose in a range boundedby any of these values, may be administered.

For a combination of an amoxapine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 10-20 mg, about 10-300 mg, about 10-250 mg, about 10-200 mg, about10-150 mg, about 10-120 mg, about 10-100 mg, about 10-80 mg, about 10-60mg, about 10-40 mg, about 20-25 mg, about 25-30 mg, about 30-40 mg,about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about140-160 mg, about 160-180 mg, about 180-200 mg, about 200-220 mg, about220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg, about280-300 mg, about 300-320 mg, about 320-350 mg, about 350-400 mg, about400-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250mg, about 300 mg, about 400 mg, of the amoxapine, or any dose in a rangebounded by any of these values, may be administered.

For a combination of a desipramine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 1-15 mg, about 10-20 mg, about 10-25 mg, about 10-30 mg, about10-40 mg, about 10-50 mg, about 10-60 mg, about 10-70 mg, about 10-80mg, about 10-90 mg, about 10-100 mg, about 10-120 mg, about 10-140 mg,about 10-150 mg, about 10-180 mg, about 10-200 mg, about 20-30 mg, about20-40 mg, about 30-40 mg, about 40-50 mg, about 40-60 mg, about 50-60mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg,about 90-110 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg,about 160-180 mg, about 180-200 mg, about 180-220 mg, about 200-220 mg,about 220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg,about 280-300 mg, about 280-320 mg, about 300-350 mg, about 350-400 mg,about 100-200 mg, about 25-100 mg, about 25 mg, about 50 mg, about 100mg, about 200 mg, about 250 mg, of the desipramine, or any dose in arange bounded by any of these values, may be administered.

For a combination of a protriptyline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 5-100mg, about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about2-14 mg, about 2-15 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg,about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about2-40 mg, about 15-60 mg, about 1-5 mg, about 5-10 mg, about 10-15 mg,about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, about35-40 mg, about 40-45 mg, about 45-50 mg, about 50-55 mg, about 55-60mg, about 60-65 mg, about 65-70 mg, about 70-80 mg, about 80-90 mg,about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg,about 160-180 mg, about 180-200 mg, about 10 mg, about 20 mg, about 30mg, about 60 mg, about 100 mg, about 150 mg, of the protriptyline, orany dose in a range bounded by any of these values, may be administered.

For a combination of a trimipramine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 20-300mg, about 1-10 mg, about 5-20 mg, about 5-25 mg, about 5-30 mg, about5-35 mg, about 5-40 mg, about 5-45 mg, about 5-50 mg, about 5-55 mg,about 5-60 mg, about 5-65 mg, about 5-70 mg, about 5-75 mg, about 5-100mg, about 5-125 mg, about 5-150 mg, about 10-20 mg, about 20-30 mg,about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about100-200 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about180-200 mg, about 180-220 mg, about 200-220 mg, about 220-240 mg, about240-250 mg, about 250-260 mg, about 260-280 mg, about 280-300 mg, about300-320 mg, about 320-350 mg, about 350-400 mg, about 400-500 mg, about10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150mg, about 250 mg, about 300 mg, of the trimipramine, or any dose in arange bounded by any of these values, may be administered.

For a combination of a nortriptyline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 5-10 mg, about 5-20 mg, about 5-25 mg, about 5-30 mg, about 5-35mg, about 5-40 mg, about 5-45 mg, about 5-50 mg, about 5-55 mg, about5-60 mg, about 5-65 mg, about 5-70 mg, about 5-75 mg, about 5-100 mg,about 5-125 mg, about 5-150 mg, about 10-15 mg, about 15-20 mg, about20-25 mg, about 20-30 mg, about 25-30 mg, about 30-35 mg, about 30-50mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about 50-150 mg,about 50-55 mg, about 55-60 mg, about 60-65 mg, about 65-70 mg, about70-80 mg, about 80-90 mg, about 80-120 mg, about 90-100 mg, about100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about180-200 mg, about 10 mg, about 20 mg, about 30 mg, about 60 mg, about100 mg, about 150 mg, of the nortriptyline, or any dose in a rangebounded by any of these values, may be administered.

For a combination of a maprotiline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 5-10 mg, about 5-20 mg, about 5-25 mg, about 5-30 mg, about 5-35mg, about 5-40 mg, about 5-45 mg, about 5-50 mg, about 5-55 mg, about5-60 mg, about 5-65 mg, about 5-70 mg, about 5-75 mg, about 5-100 mg,about 5-125 mg, about 5-150 mg, about 10-15 mg, about 10-250 mg, about10-75 mg, about 10-50 mg, about 15-20 mg, about 20-25 mg, about 25-30mg, about 30-35 mg, about 35-40 mg, about 40-45 mg, about 45-50 mg,about 50-55 mg, about 55-60 mg, about 60-65 mg, about 60-90 mg, about65-70 mg, about 70-75 mg, about 75-80 mg, about 80-85 mg, about 80-120mg, about 85-90 mg, about 90-100 mg, about 100-120 mg, about 100-150 mg,about 120-125 mg, about 125-140 mg, about 140-150 mg, about 150-160 mg,about 160-180 mg, about 180-200 mg, about 200-225 mg, about 210-240 mg,about 200-250 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg,about 75 mg, about 100 mg, about 150 mg, about 225 mg, of themaprotiline, or any dose in a range bounded by any of these values, maybe administered.

For a combination of a phenelzine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 5-10 mg, about 5-20 mg, about 5-25 mg, about 5-30 mg, about 5-35mg, about 5-40 mg, about 5-45 mg, about 5-50 mg, about 5-55 mg, about5-60 mg, about 5-65 mg, about 5-70 mg, about 5-75 mg, about 5-90 mg,about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about30-35 mg, about 35-40 mg, about 40-45 mg, about 40-50 mg, about 45-50mg, about 50-55 mg, about 50-70 mg, about 50-200 mg, about 55-60 mg,about 60-65 mg, about 60-90 mg, about 65-70 mg, about 70-80 mg, about80-90 mg, 80-120 mg, about 90-100 mg, about 100-120 mg, about 100-150mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about 180-200mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 100 mg,about 150 mg, of the phenelzine, or any dose in a range bounded by anyof these values, may be administered.

For a combination of a isocarboxazid and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg,about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg,about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about2-45 mg, about 2-50 mg, about 2-55 mg, about 2-60 mg, about 5-10 mg,about 5-15 mg, about 10-15 mg, about 10-60 mg, about 15-20 mg, about20-25 mg, about 25-30 mg, about 30-35 mg, about 30-50 mg, about 35-40mg, about 40-45 mg, about 45-50 mg, about 50-55 mg, about 50-70 mg,about 55-60 mg, about 60-65 mg, about 65-70 mg, about 70-80 mg, about80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about140-160 mg, about 160-180 mg, about 180-200 mg, about 10 mg, about 15mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, of theisocarboxazid, or any dose in a range bounded by any of these values,may be administered.

For a combination of a tranylcypromine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 1-30 mg, about 1-25 mg, about 1-20 mg, about 2-5 mg, about 2-6 mg,about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg,about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg,about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30mg, about 2-35 mg, about 2-40 mg, about 2-45 mg, about 2-50 mg, about2-55 mg, about 2-60 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg,about 20-25 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg, about40-45 mg, about 45-50 mg, about 50-55 mg, about 55-60 mg, about 60-65mg, about 65-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg,about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg,about 180-200 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg,about 100 mg, about 150 mg, of the tranylcypromine, or any dose in arange bounded by any of these values, may be administered.

For a combination of a paroxetine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 1-50 mg, about 1-20 mg, about 1-15 mg, about 1-10 mg, about 2-5mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg,about 2-20 mg, about 2-30 mg, about 2-40 mg, about 2-50 mg, about 5-10mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg,about 30-35 mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about50-55 mg, about 55-60 mg, about 60-65 mg, about 65-70 mg, about 70-80mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg,about 140-160 mg, about 160-180 mg, about 180-200 mg, about 10 mg, about15 mg, about 20 mg, about 30 mg, about 60 mg, about 100 mg, about 150mg, of the paroxetine, or any dose in a range bounded by any of thesevalues, may be administered.

For a combination of a trazodone and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 10-20 mg, about 10-30 mg, about 10-40 mg, about 10-50 mg, about10-60 mg, about 10-70 mg, about 10-80 mg, about 10-90 mg, about 10-100mg, about 10-120 mg, about 10-140 mg, about 10-150 mg, about 10-180 mg,about 10-200 mg, about 10-250 mg, about 10-300 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about250 mg, about 300 mg, about 400 mg, about 600 mg, of the trazodone, orany dose in a range bounded by any of these values, may be administered.

For a combination of a citalopram and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 1-20 mg, about 1-15 mg, about 1-10 mg, about 2-5 mg, about 2-6 mg,about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg,about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-20mg, about 2-25 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg,about 30-35 mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about50-55 mg, about 55-60 mg, about 60-65 mg, about 65-70 mg, about 70-80mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg,about 140-160 mg, about 160-180 mg, about 180-200 mg, about 10 mg, about15 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg,about 150 mg, of the citalopram, or any dose in a range bounded by anyof these values, may be administered.

For a combination of a sertraline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 1-50 mg, about 1-45 mg, about 1-40 mg, about 1-30 mg, about 1-20mg, about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg,about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg,about 2-45 mg, about 2-50 mg, about 5-10 mg, about 10-15 mg, about 15-20mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg,about 40-45 mg, about 45-50 mg, about 50-55 mg, about 55-60 mg, about60-65 mg, about 65-70 mg, about 70-75 mg, about 75-80 mg, about 80-85mg, about 85-90 mg, about 90-100 mg, about 100-120 mg, about 120-125 mg,about 125-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-300 mg, about 10 mg, about 25 mg, about 30mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg,about 225 mg, of sertraline, or any dose in a range bounded by any ofthese values, may be administered.

For a combination of an aryloxy indanamine and a dextromethorphan(including deuterium-modified dextromethorphan, e.g.d6-dextromethorphan, and non-deuterium modified dextromethorphan), adaily dose of about 0.1-0.25 mg, about 0.25-0.5 mg, about 0.5-0.75 mg,about 0.75-1 mg, about 1-5 mg, about 5-10 mg, about 10-15 mg, about15-20 mg, about 20-25 mg, about 25-30 mg, about 30-40 mg, about 40-50mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg,about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-150 mg,about 150-160 mg, about 160-180 mg, about 180-200 mg, about 200-220 mg,about 220-240, about 240-250 mg, about 250-260 mg, about 260-280 mg,about 280-300 mg, about 300-320 mg, about 320-350 mg, about 350-400 mg,about 400-450 mg, about 450-500 mg, about 500-550 mg, about 550-600 mg,about 600-650 mg, about 650-700 mg, about 700-800 mg, about 800-1000 mg,about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about250 mg, about 300 mg, about 400 mg, about 600 mg, of the aryloxyindanamine, or any dose in a range bounded by any of these values, maybe administered.

For a combination of a benactyzine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the benactyzine, or any dose in a range bounded byany of these values, may be administered.

For a combination of a escitalopram and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg,about 2-10 mg, about 2-12 mg, about 2-14 mg, about 2-15 mg, about 2-20mg, about 5-10 mg, about 5-15 mg, about 10-15 mg, about 10-30 mg, about15-20 mg, about 15-30 mg, about 20-25 mg, about 25-30 mg, about 30-35mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about 50-55 mg,about 55-60 mg, about 60-65 mg, about 65-70 mg, about 70-80 mg, about80-90 mg, about 90-100 mg, about 100-200 mg, about 5 mg, about 10 mg,about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about40 mg, about 50 mg, of the escitalopram, or any dose in a range boundedby any of these values, may be administered.

For a combination of a fluvoxamine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of 50-300 mg,1-10 mg, about 10-20 mg, about 10-30 mg, about 10-40 mg, about 10-50 mg,about 10-60 mg, about 10-70 mg, about 10-80 mg, about 10-90 mg, about10-100 mg, about 10-120 mg, about 10-140 mg, about 10-150 mg, about10-180 mg, about 10-200 mg, about 10-250 mg, about 10-300 mg, about20-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 90-110 mg,about 100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg,about 180-200 mg, about 180-220 mg, about 200-220 mg, about 220-240,about 240-250 mg, about 240-260 mg, about 250-260 mg, about 260-280 mg,about 280-300 mg, about 280-320 mg, about 300-320 mg, about 320-350 mg,about 350-400 mg, about 400-500 mg, about 10 mg, about 25 mg, about 50mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg,of the fluvoxamine, or any dose in a range bounded by any of thesevalues, may be administered.

For a combination of a venlafaxine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 5-20 mg, about 5-25 mg, about 5-30 mg, about 5-35 mg, about 5-40mg, about 5-45 mg, about 5-50 mg, about 5-55 mg, about 5-60 mg, about5-65 mg, about 5-70 mg, about 5-75 mg, about 5-100 mg, about 5-125 mg,about 5-150 mg, about 10-20 mg, about 20-25 mg, about 25-30 mg, about30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80mg, about 80-90 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg,about 140-150 mg, about 120-180 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 225, about 250 mg, about 375 mg,about 400 mg, about 600 mg, of the venlafaxine, or any dose in a rangebounded by any of these values, may be administered.

For a combination of a desvenlafaxine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 2-5 mg,about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg,about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about2-24 mg, about 2-25 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg,about 2-45 mg, about 2-50 mg, about 2-75 mg, about 2-100 mg, about 1-5mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about20-30 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg, about 40-45mg, about 40-60 mg, about 45-50 mg, about 50-55 mg, about 55-60 mg,about 60-65 mg, about 65-70 mg, about 70-80 mg, about 80-90 mg, about80-120 mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about140-160 mg, about 160-180 mg, about 180-200 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg,about 150 mg, of the desvenlafaxine, or any dose in a range bounded byany of these values, may be administered.

For a combination of a duloxetine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg,about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14mg, about 2-15 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg,about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40mg, about 2-45 mg, about 2-60 mg, about 2-90 mg, about 2-120 mg, about5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 20-40 mg,about 25-30 mg, about 30-35 mg, about 30-50 mg, about 35-40 mg, about40-45 mg, about 45-50 mg, about 50-55 mg, about 50-70 mg, about 55-60mg, about 60-65 mg, about 65-70 mg, about 70-80 mg, about 80-90 mg,about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg,about 160-180 mg, about 180-200 mg, about 10 mg, about 15 mg, about 20mg, about 30 mg, about 40 mg, about 60 mg, about 100 mg, about 120 mg,of the duloxetine, or any dose in a range bounded by any of thesevalues, may be administered.

For a combination of a mirtazapine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 2-5 mg,about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg,about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15mg, about 2-20 mg, about 2-25 mg, about 2-30 mg, about 2-35 mg, about2-40 mg, about 2-45 mg, about 1-5 mg, about 5-10 mg, about 5-100 mg,about 10-15 mg, about 10-50 mg, about 15-20 mg, about 15-45 mg, about20-25 mg, about 25-30 mg, about 30-35 mg, about 35-40 mg, about 40-45mg, about 45-50 mg, about 50-55 mg, about 55-60 mg, about 60-65 mg,about 65-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about100-120 mg, about 120-140 mg, about 140-160 mg, about 160-180 mg, about180-200 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40mg, about 45 mg, about 60 mg, about 75 mg, of the mirtazapine, or anydose in a range bounded by any of these values, may be administered.

For a combination of a nefazodone and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 10-20 mg, about 20-40 mg, about 20-50 mg, about 20-60 mg, about20-70 mg, about 20-80 mg, about 20-90 mg, about 20-100 mg, about 20-120mg, about 20-140 mg, about 20-160 mg, about 20-180 mg, about 20-200 mg,about 20-250 mg, about 20-300 mg, about 20-450 mg, about 20-600 mg,about 20-25 mg, about 25-30 mg, about 30-40 mg, about 40-50 mg, about50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 80-120mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 140-150mg, about 150-160 mg, about 160-180 mg, about 160-240 mg, about 180-200mg, about 200-220 mg, about 220-240 mg, about 240-250 mg, about 250-260mg, about 260-280 mg, about 280-300 mg, about 300-320 mg, about 320-350mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 500-550mg, about 550-600 mg, about 600-650 mg, about 650-700 mg, about 700-1000mg, about 1000-1500 mg, about 25 mg, about 50 mg, about 75 mg, about 100mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 600mg, of the nefazodone, or any dose in a range bounded by any of thesevalues, may be administered.

For a combination of a selegiline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.5-2mg, about 2-5 mg, about 1-10 mg, about 1-9 mg, about 1-8 mg, about 1-7mg, about 1-6 mg, about 1-5 mg, about 1-3 mg, about 3-5 mg, about 5-10mg, about 5-15 mg, about 10-15 mg, about 15-25 mg, about 25-30 mg, about30-35 mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about 5 mg,about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, of theselegiline, or any dose in a range bounded by any of these values, maybe administered.

For a combination of a sibutramine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-5 mg,about 1-15 mg, about 1-10 mg, about 1-8 mg, about 5-10 mg, about 10-15mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg,about 35-40 mg, about 40-45 mg, about 45-50 mg, about 50-55 mg, about55-60 mg, about 60-65 mg, about 65-70 mg, about 70-80 mg, about 80-90mg, about 90-100 mg, about 100-120 mg, about 120-140 mg, about 5 mg,about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about60 mg, about 100 mg, about 120 mg, of the sibutramine, or any dose in arange bounded by any of these values, may be administered.

For a combination of a rasagiline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.3mg, about 0.3-0.5 mg, about 0.3-0.7 mg, about 0.5-0.7 mg, about 0.5-1.5mg, about 0.7-0.9 mg, about 0.9-1.0 mg, about 1.0-1.5 mg, about 1.5-2.0mg, about 2.0-3.0 mg, about 0.1 mg, about 0.25 mg, about 0.5 mg, about0.75 mg, about 1 mg, about 2 mg, of the rasagiline, or any dose in arange bounded by any of these values, may be administered.

For a combination of a milnacipran and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-7.5mg, about 7.5-12.5 mg, about 5-20 mg, about 5-100 mg, about 5-90 mg,about 5-80 mg, about 5-70 mg, about 5-60 mg, about 5-50 mg, about 5-40mg, about 12.5-15 mg, about 15-20 mg, about 20-30 mg, about 20-25 mg,about 25-30 mg, about 30-35 mg, about 35-40 mg, about 40-45 mg, about45-50 mg, about 50-55 mg, about 40-60 mg, about 55-60 mg, about 60-65mg, about 65-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg,about 80-120 mg, about 100-120 mg, about 120-140 mg, about 140-160 mg,about 160-180 mg, about 180-200 mg, about 180-220 mg, about 200-300 mg,about 300-400 mg, about 7.5 mg, about 12.5 mg, about 25 mg, about 50 mg,about 75 mg, about 60 mg, about 100 mg, about 200 mg, of themilnacipran, or any dose in a range bounded by any of these values, maybe administered.

For a combination of a moclobemide and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 1-10 mg,about 10-20 mg, about 20-25 mg, about 20-450 mg, about 20-300 mg, about20-250 mg, about 20-200 mg, about 20-150 mg, about 20-100 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-320 mg, about 280-300 mg,about 300-320 mg, about 320-350 mg, about 350-400 mg, about 430-470 mg,about 400-450 mg, about 450-500 mg, about 500-550 mg, about 550-600 mg,about 600-650 mg, about 650-700 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the moclobemide, or any dose in a range bounded byany of these values, may be administered.

For a combination of a nialamide and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the nialamide, or any dose in a range bounded byany of these values, may be administered.

For a combination of a iproniazid and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the iproniazid, or any dose in a range bounded byany of these values, may be administered.

For a combination of a iproclozide and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the iproclozide, or any dose in a range bounded byany of these values, may be administered.

For a combination of a toloxatone and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the toloxatone, or any dose in a range bounded byany of these values, may be administered.

For a combination of a butriptyline and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the butriptyline, or any dose in a range bounded byany of these values, may be administered.

For a combination of a dosulepin and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the dosulepin, or any dose in a range bounded byany of these values, may be administered.

For a combination of a dibenzepin and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the dibenzepin, or any dose in a range bounded byany of these values, may be administered.

For a combination of a iprindole and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the iprindole, or any dose in a range bounded byany of these values, may be administered.

For a combination of a lofepramine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the lofepramine, or any dose in a range bounded byany of these values, may be administered.

For a combination of a opipramol and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the opipramol, or any dose in a range bounded byany of these values, may be administered.

For a combination of a norfluoxetine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the norfluoxetine, or any dose in a range boundedby any of these values, may be administered.

For a combination of a dapoxetine and a dextromethorphan (includingdeuterium-modified dextromethorphan, e.g. d6-dextromethorphan, andnon-deuterium modified dextromethorphan), a daily dose of about 0.1-0.25mg, about 0.25-0.5 mg, about 0.5-0.75 mg, about 0.75-1 mg, about 1-5 mg,about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about25-30 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-120 mg,about 120-140 mg, about 140-150 mg, about 150-160 mg, about 160-180 mg,about 180-200 mg, about 200-220 mg, about 220-240 mg, about 240-250 mg,about 250-260 mg, about 260-280 mg, about 280-300 mg, about 300-320 mg,about 320-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg,about 500-550 mg, about 550-600 mg, about 600-650 mg, about 650-700 mg,about 700-800 mg, about 800-1000 mg, about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, about 400mg, about 600 mg, of the dapoxetine, or any dose in a range bounded byany of these values, may be administered.

Bupropion has the structure shown below (bupropion hydrochloride formshown).

Combining bupropion with dextromethorphan may provide greater efficacy,such as greater pain relief, than would otherwise be achieved byadministering either component alone. In extensive metabolizers,dextromethorphan can be rapidly and extensively metabolized, yieldinglow systemic exposure even at high doses. Bupropion, besides possessinganti-depressant and analgesic properties, is an inhibitor ofdextromethorphan metabolism. Bupropion is a dopamine and norepinephrinereuptake inhibitor. It can also be a nicotinic acetylcholine receptorantagonist, and it can modulate cytokines associated with inflammatorydiseases. Bupropion can affect levels of tumor necrosis factor-alpha andinterferon-gamma. Metabolites of bupropion, which includehydroxybupropion, threohydroxybupropion (also known asthreohydrobupropion or threodihydrobupropion), anderythrohydroxybupropion (also known as erythrohydrobupropion orerythrodihydrobupropion), are also inhibitors of dextromethorphanmetabolism. Thus, bupropion, including a form of bupropion that israpidly converted in the body (such as a salt, hydrate, solvate,polymorph, etc.), is a prodrug of hydroxybupropion,threohydroxybupropion, and erythrohydroxybupropion. Prodrugs ofbupropion can include N-methylbupropion and N-benzylbupropion.

As explained above, this inhibition may augment dextromethorphan plasmalevels, resulting in additive or synergistic efficacy such as relief ofneurological disorders including pain, depression, smoking cessation,etc. Thus, while inhibition of dextromethorphan metabolism is only oneof many potential benefits of the combination, co-administration ofdextromethorphan with bupropion may thereby enhance the efficacy ofbupropion for many individuals. Co-administration of dextromethorphanwith bupropion may enhance the analgesic properties of bupropion formany individuals. Co-administration of dextromethorphan with bupropionmay also enhance the antidepressant properties of bupropion for manyindividuals, including faster onset of action.

Another potential benefit of co-administration of dextromethorphan andbupropion is that it may be useful to reduce the potential for anadverse event, such as somnolence, associated with treatment bydextromethorphan. This may be useful, for example, in human patients atrisk of experiencing the adverse event as a result of being treated withdextromethorphan.

Another potential benefit of co-administration of dextromethorphan andbupropion is that it may be useful to reduce the potential for anadverse event, such as seizure, associated with treatment by bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds. This may be useful, forexample, in human patients at risk of experiencing the adverse event asa result of being treated with bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

With respect to dextromethorphan, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, co-administration may reduce acentral nervous system adverse event, a gastrointestinal event, oranother type of adverse event associated with any of these compounds.Central nervous system (CNS) adverse events include, but are not limitedto, nervousness, dizziness, sleeplessness, light-headedness, tremor,hallucinations, convulsions, CNS depression, fear, anxiety, headache,increased irritability or excitement, tinnitus, drowsiness, dizziness,sedation, somnolence, confusion, disorientation, lassitude,incoordination, fatigue, euphoria, nervousness, insomnia, sleepingdisturbances, convulsive seizures, excitation, catatonic-like states,hysteria, hallucinations, delusions, paranoia, headaches and/ormigraine, and extrapyramidal symptoms such as oculogyric crisis,torticollis, hyperexcitability, increased muscle tone, ataxia, and/ortongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea,vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominaldistension, flatulence, peptic ulcers with bleeding, loose stools,constipation, stomach pain, heartburn, gas, loss of appetite, feeling offullness in stomach, indigestion, bloating, hyperacidity, dry mouth,gastrointestinal disturbances, and gastric pain.

Co-administering dextromethorphan and an antidepressant, such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, does not necessarily require that the two compounds beadministered in the same dosage form. For example, the two compounds maybe administered in a single dosage form, or they may be administered intwo separate dosage forms. Additionally, the two compounds may beadministered at the same time, but this is not required. The compoundscan be given at different times as long as both are in a human body atthe same time for at least a portion of the time that treatment byco-administration is being carried out.

Side effects of bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, and/or dextromethorphan may be reduced byadministering bupropion, hydroxybupropion, erythrohydroxybupropion, orthreohydroxybupropion, with dextromethorphan. Examples of side effectsthat may be reduced include abnormal sensation of rotation and movement,agitation, arm weakness, bloating, blurred vision, burning sensation inthe eyes, buzzing sound(s) in the ear(s), changes in vital signs(including, but not limited to, heart rate, respiratory rate, bodytemperature, and blood pressure), cold sensation, constipation,difficulty concentrating, difficulty sleeping, difficulty in fallingasleep, difficulty urinating, difficulty with bowel movement, discomfortin the ear, discomfort in the eye, discomfort in the stomach, dizziness,dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feelingfeverish, feeling heavy headed, feeling more agitated than usual,feeling more tired than usual, feeling tired, hand tremors, handweakness, headache, heartburn, hot flashes, increased blood pressure,increased skin sensitivity, increased skin sensitivity at head and face,involuntary muscle contraction, involuntary muscle contractions all overthe body, knee pain, leg weakness, lightheadedness, loose stool, loss ofappetite, low back pain, menstrual disorder, metallic taste, more salivathan usual, mucosal dryness, nasal congestion, nausea, runny nose,sensation of light pressure sensation in the eyes, shivers whenstretching or yawning, skin sensitivity, skin sensitivity in arm, face,and/or head, sleep difficulties, soft stools, stomach ache, stomachdiscomfort, sweaty hands and/or feet, throat irritation, throat pain,tinnitus, tremors, and/or weakness. Any of these side effects may alsobe referred to, or grouped, according to a corresponding, equivalent, orotherwise relevant term found in the Medical Dictionary for RegulatoryActivities (MedRA).

In some embodiments, co-administration of a combination of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, and dextromethorphanresults in both bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan contributing to the pain relievingproperties of the combination. For example, the combination may haveimproved pain relieving properties as compared to bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, alone or compared todextromethorphan alone, including potentially faster onset of action.

In some embodiments, the combination may have improved pain relievingproperties of at least about 0.5%, at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%,about 10% to about 20%, about 20% to about 30%, about 30% to about 40%,about 40% to about 50%, about 50% to about 60%, about 60% to about 70%,about 70% to about 80%, about 80% to about 90%, about 90% to about 100%,about 100% to about 110%, about 110% to about 120%, about 120% to about130%, about 130% to about 140%, about 140% to about 150%, about 150% toabout 160%, about 160% to about 170%, about 170% to about 180%, about180% to about 190%, about 190% to about 200%, or any amount of painrelief in a range bounded by, or between, any of these values, ascompared to bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, alone.

In some embodiments, the combination may have improved pain relievingproperties of at least about 0.5%, at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%,about 10% to about 20%, about 20% to about 30%, about 30% to about 40%,about 40% to about 50%, about 50% to about 60%, about 60% to about 70%,about 70% to about 80%, about 80% to about 90%, about 90% to about 100%,about 100% to about 110%, about 110% to about 120%, about 120% to about130%, about 130% to about 140%, about 140% to about 150%, about 150% toabout 160%, about 160% to about 170%, about 170% to about 180%, about180% to about 190%, about 190% to about 200%, or any amount of painrelief in a range bounded by, or between, any of these values, ascompared to as compared to dextromethorphan alone.

Unless otherwise indicated, any reference to a compound herein, such asdextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, by structure, name, or any other means, includespharmaceutically acceptable salts; alternate solid forms, such aspolymorphs, solvates, hydrates, etc.; tautomers; deuterium-modifiedcompounds, such as deuterium modified dextromethorphan; or any chemicalspecies that may rapidly convert to a compound described herein underconditions in which the compounds are used as described herein.

In some embodiments, an excess of one stereoisomer of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be administered. Inother embodiments, an excess of the S-enantiomer (such as at least 60%,at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 99% or enantiomerically pure S-enantiomer) or anexcess of the R-enantiomer (such as at least 60%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, at least99% or enantiomerically pure R-enantiomer) of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be administered.

Examples of deuterium-enriched bupropion, and/or enantiopuredeuterium-enriched bupropion include, but are not limited to, thoseshown below.

In some embodiments, both dextromethorphan and bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, ametabolite, or prodrug of any of these compounds are formulated to beimmediate release, and in other embodiments both bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, ametabolite or prodrug of any of these compounds are formulated to besustained release.

Examples of deuterium modified dextromethorphan include, but are notlimited to, those shown below.

A dosage form or a composition may be a blend or mixture ofdextromethorphan and a compound that inhibits the metabolism ofdextromethorphan, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, either alone or within a vehicle. Forexample, dextromethorphan and bupropion may be dispersed within eachother or dispersed together within a vehicle. A dispersion may include amixture of solid materials wherein small individual particles aresubstantially one compound, but the small particles are dispersed withinone another, such as might occur if two powders of two different drugsare blended with a solid vehicle material, and the blending is done inthe solid form. In some embodiments, dextromethorphan and bupropion maybe substantially uniformly dispersed within a composition or dosageform. Alternatively, dextromethorphan and bupropion may be in separatedomains or phases within a composition or dosage form. For example, onedrug may be in a coating and another drug may be in a core within thecoating. For example, one drug may be formulated for sustained releaseand another drug may be formulated for immediate release.

Some embodiments include administration of a tablet that containsbupropion in a form that provides sustained release and dextromethorphanin a form that provides immediate release. While there are many waysthat sustained release of bupropion may be achieved, in some embodimentsbupropion is combined with hydroxypropyl methylcellulose. For example,particles of bupropion hydrochloride could be blended withmicrocrystalline cellulose and hydroxypropyl methylcellulose (e.g.,METHOCEL®) to form an admixture of blended powders. This could then becombined with immediate release dextromethorphan in a single tablet.

Dextromethorphan and/or an antidepressant, such as bupropion,hydroxybupropion, threohydroxybupropion and erythrohydroxybupropion, ora non-bupropion antidepressant (all of which are referred tocollectively herein as “therapeutic compounds” for convenience) may becombined with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice asdescribed, for example, in Remington's Pharmaceutical Sciences, 2005.The relative proportions of active ingredient and carrier may bedetermined, for example, by the solubility and chemical nature of thecompounds, chosen route of administration and standard pharmaceuticalpractice.

Therapeutic compounds may be administered by any means that may resultin the contact of the active agent(s) with the desired site or site(s)of action in the body of a patient. The compounds may be administered byany conventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. For example, they may be administeredas the sole active agents in a pharmaceutical composition, or they canbe used in combination with other therapeutically active ingredients.

Therapeutic compounds may be administered to a human patient in avariety of forms adapted to the chosen route of administration, e.g.,orally or parenterally. Parenteral administration in this respectincludes administration by the following routes: intravenous,intramuscular, subcutaneous, intraocular, intrasynovial, transepithelialincluding transdermal, ophthalmic, sublingual and buccal; topicallyincluding ophthalmic, dermal, ocular, rectal and nasal inhalation viainsufflation, aerosol and rectal systemic.

The ratio of dextromethorphan to bupropion may vary. In someembodiments, the weight ratio of dextromethorphan to bupropion may beabout 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or anyratio in a range bounded by, or between, any of these values. A ratio of0.1 indicates that the weight of dextromethorphan is 1/10 that ofbupropion. A ratio of 10 indicates that the weight of dextromethorphanis 10 times that of bupropion.

The amount of dextromethorphan in a therapeutic composition may vary.For example, some liquid compositions may comprise about 0.0001% (w/v)to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% toabout 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v)to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) toabout 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) toabout 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) toabout 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) toabout 40% (w/v), or about 40% (w/v) to about 50% (w/v) ofdextromethorphan.

Some liquid dosage forms may contain about 10 mg to about 500 mg, about30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40mg to about 50 mg, about 40 mg to about 55 mg, about 40 mg to about 42mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mgto about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg,about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg,about 60 mg, about 90 mg, about 120 mg, or about 180 mg ofdextromethorphan, or any amount of dextromethorphan in a range boundedby, or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan.

Some solid dosage forms may contain about 10 mg to about 500 mg, about30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mgto about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120mg, or about 180 mg of dextromethorphan, or any amount ofdextromethorphan in a range bounded by, or between, any of these values.

In some embodiments, the amount of dextromethorphan may range from about0.1 mg/kg to about 20 mg/kg, about 0.75 mg/kg to about 7.5 mg/kg, about0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.3mg/kg to about 0.9 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.6mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.8 mg/kg, about 0.75mg/kg, about 0.4 mg/kg to about 1.5 mg/kg, about 1 mg/kg to about 2mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 mg/kg to about 17mg/kg, about 15 mg/kg to about 20 mg/kg, about 1 mg/kg, about 1 mg/kg toabout 10 mg/kg, or any value bounded by or in between these ranges basedon the body weight of the patient.

The amount of bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, in a therapeutic composition may vary. If increasing theplasma level of dextromethorphan is desired, bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, should be administeredin an amount that increases the plasma level of dextromethorphan. Forexample, bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, may be administered in an amount that results in a plasmaconcentration of dextromethorphan in the human being, on day 8, day 9,or day 10, that is at least about 2 times, at least about 5 times, atleast about 10 times, at least about 15 times, at least about 20 times,at least about 30 times, at least about 40 times, at least about 50times, at least about 60 times, at least about 70 times, or at leastabout 80 times, the plasma concentration of the same amount ofdextromethorphan administered without bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may be administered to a human beingin an amount that results in a 12 hour area under the curve from thetime of dosing (AUC₀₋₁₂), or average plasma concentration in the humanbeing for the 12 hours following dosing (C_(avg)) of dextromethorphan,on day 8, day 9, or day 10, that is at least about 2 times, at leastabout 5 times, at least about 10 times, at least about 15 times, atleast about 20 times, at least about 30 times, at least about 40 times,at least about 50 times, at least about 60 times, at least about 70times, or at least about 80 times the plasma concentration of the sameamount of dextromethorphan administered without bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may be administered to a human beingin an amount that results in a maximum plasma concentration (C_(max)) ofdextromethorphan in the human being, on day 8, day 9, or day 10, that isat least about 2 times, at least about 5 times, at least about 10 times,at least about 15 times, at least about 20 times, at least about 30times, or at least about 40 times the plasma concentration of the sameamount of dextromethorphan administered without bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

For co-administration of bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, an increase in the dextromethorphanplasma level can occur on the first day that bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, is administered, ascompared to the same amount of dextromethorphan administered withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds. For example, the dextromethorphan plasma level on the firstday that bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 times, at leastabout at least 2 times, at least about 2.5 times, at least about 3times, at least about 4 times, at least about 5 times, at least about 6times at least about 7 times, at least about 8 times, at least about 9times, or at least about 10 times the level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, the dextromethorphan AUC on the first day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least twicethe AUC that would be achieved by administering the same amount ofdextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextromethorphan AUC₀₋₁₂ on the first day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about15 ng·hr/mL, at least about 17 ng·hr/mL, at least about 19 ng·hr/mL, atleast about 20 ng·hr/mL, at least about 22 ng·hr/mL, at least about 23ng·hr/mL, at least about 24 ng·hr/mL, at least about 25 ng·hr/mL, atleast about 26 ng·hr/mL, at least about 27 ng·hr/mL, at least about 28ng·hr/mL, at least about 29 ng·hr/mL, at least about 30 ng·hr/mL, atleast about 31 ng·hr/mL, at least about 32 ng·hr/mL, at least about 33ng·hr/mL, at least about 34 ng·hr/mL, at least about 35 ng·hr/mL, atleast about 36 ng·hr/mL, at least about 37 ng·hr/mL, at least about 38ng·hr/mL, at least about 39 ng·hr/mL, at least about 40 ng·hr/mL, atleast about 41 ng·hr/mL, at least about 42 ng·hr/mL, at least about 43ng·hr/mL, at least about 44 ng·hr/mL, at least about 45 ng·hr/mL, atleast about 46 ng·hr/mL, at least about 47 ng·hr/mL, at least about 48ng·hr/mL, at least about 49 ng·hr/mL, at least about 50 ng·hr/mL, atleast about 51 ng·hr/mL, at least about 52 ng·hr/mL, at least about 53ng·hr/mL, at least about 54 ng·hr/mL, at least about 55 ng·hr/mL, atleast about 56 ng·hr/mL, at least about or 56.7 ng·hr/mL, and may be upto 10,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₁₂ on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about40 ng·hr/mL, at least about 50 ng·hr/mL, at least about 60 ng·hr/mL, atleast about 70 ng·hr/mL, at least about 80 ng·hr/mL, at least about 90ng·hr/mL, at least about 100 ng·hr/mL, at least about 150 ng·hr/mL, atleast about 200 ng·hr/mL, at least about 250 ng·hr/mL, at least about300 ng·hr/mL, at least about 350 ng·hr/mL, at least about 400 ng·hr/mL,at least about 450 ng·hr/mL, at least about 500 ng·hr/mL, at least about550 ng·hr/mL, about 500 ng·hr/mL to about 600 ng·hr/mL, about 500ng·hr/mL to about 550 ng·hr/mL, about 500 ng·hr/mL to about 525ng·hr/mL, about 525 ng·hr/mL to about 600 ng·hr/mL, at least about 600ng·hr/mL, at least about 650 ng·hr/mL, at least about 700 ng·hr/mL, atleast about 750 ng·hr/mL, at least about 800 ng·hr/mL, about 800ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL to about 900ng·hr/mL, about 850 ng·hr/mL to about 875 ng·hr/mL, about 875 ng·hr/mLto about 900 ng·hr/mL, about 900 ng·hr/mL to about 1,000 ng·hr/mL, about1,000 ng·hr/mL to about 1,100 ng·hr/mL, about 1,100 ng·hr/mL to about1,200 ng·hr/mL, about 1,200 ng·hr/mL to about 1,300 ng·hr/mL, about1,300 ng·hr/mL to about 1,400 ng·hr/mL, about 1,400 ng·hr/mL to about1,500 ng·hr/mL, about 1,500 ng·hr/mL to about 1,600 ng·hr/mL, about1,600 ng·hr/mL to about 1,700 ng·hr/mL, about 1,700 ng·hr/mL to about1,800 ng·hr/mL, about 1,800 ng·hr/mL to about 2,000 ng·hr/mL, at leastabout 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about 950ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050 ng·hr/mL, atleast about 1100 ng·hr/mL, at least about 1150 ng·hr/mL, at least about1200 ng·hr/mL, at least about 1250 ng·hr/mL, at least about 1300ng·hr/mL, at least about 1350 ng·hr/mL, at least about 1400 ng·hr/mL, atleast about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, at least about1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1625ng·hr/mL, at least about 1650 ng·hr/mL, at least about 1675 ng·hr/mL, orat least about 1686.3 ng·hr/mL, and, in some embodiments, may be up toabout 50,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₂₄ on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about50 ng·hr/mL, at least about 75 ng·hr/mL, at least about 100 ng·hr/mL, atleast about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about400 ng·hr/mL, at least about 500 ng·hr/mL, at least about 600 ng·hr/mL,at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, atleast about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800ng·hr/mL, at least about 1900 ng·hr/mL, at least about 2000 ng·hr/mL, atleast about 2100 ng·hr/mL, at least about 2200 ng·hr/mL, at least about2300 ng·hr/mL, at least about 2400 ng·hr/mL, at least about 2500ng·hr/mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, atleast about 2800 ng·hr/mL, at least about 1850 ng·hr/mL, at least about2900 ng·hr/mL, at least about 2950 ng·hr/mL, or at least about 2975.3ng·hr/mL, and, in some embodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC_(0-inf) on the eighth daythat the dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200 ng·hr/mL,at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about500 ng·hr/mL, at least about 600 ng·hr/mL, at least about 700 ng·hr/mL,at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, atleast about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about 1900ng·hr/mL, at least about 2000 ng·hr/mL, at least about 2100 ng·hr/mL, atleast about 2200 ng·hr/mL, at least about 2300 ng·hr/mL, at least about2400 ng·hr/mL, at least about 2500 ng·hr/mL, at least about 2600ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, atleast about 2900 ng·hr/mL, at least about 3000 ng·hr/mL, at least about3100 ng·hr/mL, at least about 3200 ng·hr/mL, at least about 3300ng·hr/mL, at least about 3400 ng·hr/mL, at least about 3500 ng·hr/mL, atleast about 3600 ng·hr/mL, at least about 3700 ng·hr/mL, at least about3800 ng·hr/mL, at least about 3900 ng·hr/mL, at least about 4000ng·hr/mL, at least about 4100 ng·hr/mL, at least about 4200 ng·hr/mL, atleast about 4300 ng·hr/mL, at least about 4400 ng·hr/mL, at least about4500 ng·hr/mL, at least about 4600 ng·hr/mL, at least about 4700ng·hr/mL, at least about 4800 ng·hr/mL, at least about 4900 ng·hr/mL, atleast about 5000 ng·hr/mL, at least about 5100 ng·hr/mL, at least about5200 ng·hr/mL, at least about 5300 ng·hr/mL, at least about 5400ng·hr/mL, at least about 5500 ng·hr/mL, at least about 5600 ng·hr/mL, atleast about 5700 ng·hr/mL, at least about 5800 ng·hr/mL, at least about5900 ng·hr/mL, at least about 6000 ng·hr/mL, at least about 6100ng·hr/mL, at least about 6200 ng·hr/mL, at least about 6300 ng·hr/mL, atleast about 6400 ng·hr/mL, at least about 6500 ng·hr/mL, at least about6600 ng·hr/mL, at least about 6700 ng·hr/mL, at least about 6800ng·hr/mL, at least about 6900 ng·hr/mL, at least about 7000 ng·hr/mL, atleast about 7100 ng·hr/mL, at least about 7150 ng·hr/mL, at least about7200 ng·hr/mL, or at least about 7237.3 ng·hr/mL, and, in someembodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₁₂ on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about40 ng·hr/mL, at least about 50 ng·hr/mL, at least about 60 ng·hr/mL, atleast about 70 ng·hr/mL, at least about 80 ng·hr/mL, at least about 90ng·hr/mL, at least about 100 ng·hr/mL, at least about 150 ng·hr/mL, atleast about 200 ng·hr/mL, at least about 250 ng·hr/mL, at least about300 ng·hr/mL, at least about 350 ng·hr/mL, at least about 400 ng·hr/mL,at least about 450 ng·hr/mL, at least about 500 ng·hr/mL, at least about550 ng·hr/mL, about 500 ng·hr/mL to about 600 ng·hr/mL, about 500ng·hr/mL to about 550 ng·hr/mL, about 500 ng·hr/mL to about 525ng·hr/mL, about 525 ng·hr/mL to about 600 ng·hr/mL, at least about 600ng·hr/mL, at least about 650 ng·hr/mL, at least about 700 ng·hr/mL, atleast about 750 ng·hr/mL, at least about 800 ng·hr/mL, about 800ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL to about 900ng·hr/mL, about 850 ng·hr/mL to about 875 ng·hr/mL, about 875 ng·hr/mLto about 900 ng·hr/mL, about 900 ng·hr/mL to about 1,000 ng·hr/mL, about1,000 ng·hr/mL to about 1,100 ng·hr/mL, about 1,100 ng·hr/mL to about1,200 ng·hr/mL, about 1,200 ng·hr/mL to about 1,300 ng·hr/mL, about1,300 ng·hr/mL to about 1,400 ng·hr/mL, about 1,400 ng·hr/mL to about1,500 ng·hr/mL, about 1,500 ng·hr/mL to about 1,600 ng·hr/mL, about1,600 ng·hr/mL to about 1,700 ng·hr/mL, about 1,700 ng·hr/mL to about1,800 ng·hr/mL, about 1,800 ng·hr/mL to about 2,000 ng·hr/mL, at leastabout 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about 950ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050 ng·hr/mL, atleast about 1100 ng·hr/mL, at least about 1150 ng·hr/mL, at least about1200 ng·hr/mL, at least about 1250 ng·hr/mL, at least about 1300ng·hr/mL, at least about 1350 ng·hr/mL, at least about 1400 ng·hr/mL, atleast about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, at least about1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1625ng·hr/mL, at least about 1650 ng·hr/mL, at least about 1675 ng·hr/mL, orat least about 1686.3 ng·hr/mL, and, in some embodiments, may be up toabout 50,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₂₄ on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about50 ng·hr/mL, at least about 75 ng·hr/mL, at least about 100 ng·hr/mL, atleast about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about400 ng·hr/mL, at least about 500 ng·hr/mL, at least about 600 ng·hr/mL,at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, atleast about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800ng·hr/mL, at least about 1900 ng·hr/mL, at least about 2000 ng·hr/mL, atleast about 2100 ng·hr/mL, at least about 2200 ng·hr/mL, at least about2300 ng·hr/mL, at least about 2400 ng·hr/mL, at least about 2500ng·hr/mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, atleast about 2800 ng·hr/mL, at least about 1850 ng·hr/mL, at least about2900 ng·hr/mL, at least about 2950 ng·hr/mL, or at least about 2975.3ng·hr/mL, and, in some embodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC_(0-inf) on the ninth daythat the dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200 ng·hr/mL,at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about500 ng·hr/mL, at least about 600 ng·hr/mL, at least about 700 ng·hr/mL,at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, atleast about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about 1900ng·hr/mL, at least about 2000 ng·hr/mL, at least about 2100 ng·hr/mL, atleast about 2200 ng·hr/mL, at least about 2300 ng·hr/mL, at least about2400 ng·hr/mL, at least about 2500 ng·hr/mL, at least about 2600ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, atleast about 2900 ng·hr/mL, at least about 3000 ng·hr/mL, at least about3100 ng·hr/mL, at least about 3200 ng·hr/mL, at least about 3300ng·hr/mL, at least about 3400 ng·hr/mL, at least about 3500 ng·hr/mL, atleast about 3600 ng·hr/mL, at least about 3700 ng·hr/mL, at least about3800 ng·hr/mL, at least about 3900 ng·hr/mL, at least about 4000ng·hr/mL, at least about 4100 ng·hr/mL, at least about 4200 ng·hr/mL, atleast about 4300 ng·hr/mL, at least about 4400 ng·hr/mL, at least about4500 ng·hr/mL, at least about 4600 ng·hr/mL, at least about 4700ng·hr/mL, at least about 4800 ng·hr/mL, at least about 4900 ng·hr/mL, atleast about 5000 ng·hr/mL, at least about 5100 ng·hr/mL, at least about5200 ng·hr/mL, at least about 5300 ng·hr/mL, at least about 5400ng·hr/mL, at least about 5500 ng·hr/mL, at least about 5600 ng·hr/mL, atleast about 5700 ng·hr/mL, at least about 5800 ng·hr/mL, at least about5900 ng·hr/mL, at least about 6000 ng·hr/mL, at least about 6100ng·hr/mL, at least about 6200 ng·hr/mL, at least about 6300 ng·hr/mL, atleast about 6400 ng·hr/mL, at least about 6500 ng·hr/mL, at least about6600 ng·hr/mL, at least about 6700 ng·hr/mL, at least about 6800ng·hr/mL, at least about 6900 ng·hr/mL, at least about 7000 ng·hr/mL, atleast about 7100 ng·hr/mL, at least about 7150 ng·hr/mL, at least about7200 ng·hr/mL, or at least about 7237.3 ng·hr/mL, and, in someembodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₁₂ on the tenth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about40 ng·hr/mL, at least about 50 ng·hr/mL, at least about 60 ng·hr/mL, atleast about 70 ng·hr/mL, at least about 80 ng·hr/mL, at least about 90ng·hr/mL, at least about 100 ng·hr/mL, at least about 150 ng·hr/mL, atleast about 200 ng·hr/mL, at least about 250 ng·hr/mL, at least about300 ng·hr/mL, at least about 350 ng·hr/mL, at least about 400 ng·hr/mL,at least about 450 ng·hr/mL, at least about 500 ng·hr/mL, at least about550 ng·hr/mL, about 500 ng·hr/mL to about 600 ng·hr/mL, about 500ng·hr/mL to about 550 ng·hr/mL, about 500 ng·hr/mL to about 525ng·hr/mL, about 525 ng·hr/mL to about 600 ng·hr/mL, at least about 600ng·hr/mL, at least about 650 ng·hr/mL, at least about 700 ng·hr/mL, atleast about 750 ng·hr/mL, at least about 800 ng·hr/mL, about 800ng·hr/mL to about 900 ng·hr/mL, about 850 ng·hr/mL to about 900ng·hr/mL, about 850 ng·hr/mL to about 875 ng·hr/mL, about 875 ng·hr/mLto about 900 ng·hr/mL, about 900 ng·hr/mL to about 1,000 ng·hr/mL, about1,000 ng·hr/mL to about 1,100 ng·hr/mL, about 1,100 ng·hr/mL to about1,200 ng·hr/mL, about 1,200 ng·hr/mL to about 1,300 ng·hr/mL, about1,300 ng·hr/mL to about 1,400 ng·hr/mL, about 1,400 ng·hr/mL to about1,500 ng·hr/mL, about 1,500 ng·hr/mL to about 1,600 ng·hr/mL, about1,600 ng·hr/mL to about 1,700 ng·hr/mL, about 1,700 ng·hr/mL to about1,800 ng·hr/mL, about 1,800 ng·hr/mL to about 2,000 ng·hr/mL, at leastabout 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about 950ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050 ng·hr/mL, atleast about 1100 ng·hr/mL, at least about 1150 ng·hr/mL, at least about1200 ng·hr/mL, at least about 1250 ng·hr/mL, at least about 1300ng·hr/mL, at least about 1350 ng·hr/mL, at least about 1400 ng·hr/mL, atleast about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, at least about1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1625ng·hr/mL, at least about 1650 ng·hr/mL, at least about 1675 ng·hr/mL, orat least about 1686.3 ng·hr/mL, and, in some embodiments, may be up toabout 50,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₂₄ on the tenth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about50 ng·hr/mL, at least about 75 ng·hr/mL, at least about 100 ng·hr/mL, atleast about 200 ng·hr/mL, at least about 300 ng·hr/mL, at least about400 ng·hr/mL, at least about 500 ng·hr/mL, at least about 600 ng·hr/mL,at least about 700 ng·hr/mL, at least about 800 ng·hr/mL, at least about900 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1100ng·hr/mL, at least about 1200 ng·hr/mL, at least about 1300 ng·hr/mL, atleast about 1400 ng·hr/mL, at least about 1500 ng·hr/mL, at least about1600 ng·hr/mL, at least about 1700 ng·hr/mL, at least about 1800ng·hr/mL, at least about 1900 ng·hr/mL, at least about 2000 ng·hr/mL, atleast about 2100 ng·hr/mL, at least about 2200 ng·hr/mL, at least about2300 ng·hr/mL, at least about 2400 ng·hr/mL, at least about 2500ng·hr/mL, at least about 2600 ng·hr/mL, at least about 2700 ng·hr/mL, atleast about 2800 ng·hr/mL, at least about 1850 ng·hr/mL, at least about2900 ng·hr/mL, at least about 2950 ng·hr/mL, or at least about 2975.3ng·hr/mL, and, in some embodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC_(0-inf) on the tenth daythat the dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200 ng·hr/mL,at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, at least about500 ng·hr/mL, at least about 600 ng·hr/mL, at least about 700 ng·hr/mL,at least about 800 ng·hr/mL, at least about 900 ng·hr/mL, at least about1000 ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1200ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400 ng·hr/mL, atleast about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, at least about1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about 1900ng·hr/mL, at least about 2000 ng·hr/mL, at least about 2100 ng·hr/mL, atleast about 2200 ng·hr/mL, at least about 2300 ng·hr/mL, at least about2400 ng·hr/mL, at least about 2500 ng·hr/mL, at least about 2600ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800 ng·hr/mL, atleast about 2900 ng·hr/mL, at least about 3000 ng·hr/mL, at least about3100 ng·hr/mL, at least about 3200 ng·hr/mL, at least about 3300ng·hr/mL, at least about 3400 ng·hr/mL, at least about 3500 ng·hr/mL, atleast about 3600 ng·hr/mL, at least about 3700 ng·hr/mL, at least about3800 ng·hr/mL, at least about 3900 ng·hr/mL, at least about 4000ng·hr/mL, at least about 4100 ng·hr/mL, at least about 4200 ng·hr/mL, atleast about 4300 ng·hr/mL, at least about 4400 ng·hr/mL, at least about4500 ng·hr/mL, at least about 4600 ng·hr/mL, at least about 4700ng·hr/mL, at least about 4800 ng·hr/mL, at least about 4900 ng·hr/mL, atleast about 5000 ng·hr/mL, at least about 5100 ng·hr/mL, at least about5200 ng·hr/mL, at least about 5300 ng·hr/mL, at least about 5400ng·hr/mL, at least about 5500 ng·hr/mL, at least about 5600 ng·hr/mL, atleast about 5700 ng·hr/mL, at least about 5800 ng·hr/mL, at least about5900 ng·hr/mL, at least about 6000 ng·hr/mL, at least about 6100ng·hr/mL, at least about 6200 ng·hr/mL, at least about 6300 ng·hr/mL, atleast about 6400 ng·hr/mL, at least about 6500 ng·hr/mL, at least about6600 ng·hr/mL, at least about 6700 ng·hr/mL, at least about 6800ng·hr/mL, at least about 6900 ng·hr/mL, at least about 7000 ng·hr/mL, atleast about 7100 ng·hr/mL, at least about 7150 ng·hr/mL, at least about7200 ng·hr/mL, or at least about 7237.3 ng·hr/mL, and, in someembodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan C_(max) on the first day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least twicethe C_(max) that would be achieved by administering the same amount ofdextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextromethorphan C_(max) on the first day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.0 ng/mL, at least about 1.5 ng/mL, at least about 2.0 ng/mL, at leastabout 2.5 ng/mL, at least about 3.0 ng/mL, at least about 3.1 ng/mL, atleast about 3.2 ng/mL, at least about 3.3 ng/mL, at least about 3.4ng/mL, at least about 3.5 ng/mL, at least about 3.6 ng/mL, at leastabout 3.7 ng/mL, at least about 3.8 ng/mL, at least about 3.9 ng/mL, atleast about 4.0 ng/mL, at least about 4.1 ng/mL, at least about 4.2ng/mL, at least about 4.3 ng/mL, at least about 4.4 ng/mL, at leastabout 4.5 ng/mL, at least about 4.6 ng/mL, at least about 4.7 ng/mL, atleast about 4.8 ng/mL, at least about 4.9 ng/mL, at least about 5.0ng/mL, at least about 5.1 ng/mL, at least about 5.2 ng/mL, at leastabout 5.3 ng/mL, at least about 5.4 ng/mL, at least about 5.5 ng/mL, atleast about 5.6 ng/mL, at least about 5.7 ng/mL, at least about 5.8ng/mL, at least about 5.9 ng/mL, at least about 6.0 ng/mL, at leastabout 6.1 ng/mL, at least about 6.2 ng/mL, at least about 6.3 ng/mL, atleast about 6.4 ng/mL, at least about 6.5 ng/mL, at least about 6.6ng/mL, at least about 6.7 ng/mL, at least about 6.8 ng/mL, at leastabout 6.9 ng/mL, at least about 7.0 ng/mL, at least about 7.1 ng/mL, atleast about 7.2 ng/mL, at least about 7.3 ng/mL, at least about 7.4ng/mL, at least about 7.5 ng/mL, at least about 7.6 ng/mL, at leastabout 7.7 ng/mL, at least about 7.8 ng/mL, at least about 7.9 ng/mL, atleast about 8.0 ng/mL, at least about 8.1 ng/mL, at least about 8.2ng/mL, at least about 8.3 ng/mL, at least about 8.4 ng/mL, at leastabout 8.5 ng/mL, at least about 8.6 ng/mL, or at least about 8.7 ng/mL,and, in some embodiments, may be up to about 1000 ng·hr/mL.

In some embodiments, the dextromethorphan C_(max) on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be about 50 ng/mLto about 60 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL toabout 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL toabout 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL toabout 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL toabout 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL toabout 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL toabout 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL toabout 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL toabout 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL toabout 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL toabout 200 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, atleast about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at leastabout 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, atleast about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL,at least about 70 ng/mL, at least about 75 ng/mL, at least about 80ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at leastabout 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, atleast about 125 ng/mL, at least about 130 ng/mL, at least about 135ng/mL, at least about 140 ng/mL, at least about 145 ng/mL, at leastabout 150 ng/mL, at least about 155 ng/mL, or at least about 158.1ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(max) on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be about 50 ng/mLto about 60 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL toabout 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL toabout 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL toabout 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL toabout 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL toabout 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL toabout 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL toabout 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL toabout 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL toabout 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL toabout 200 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, atleast about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at leastabout 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, atleast about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL,at least about 70 ng/mL, at least about 75 ng/mL, at least about 80ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at leastabout 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, atleast about 125 ng/mL, at least about 130 ng/mL, at least about 135ng/mL, at least about 140 ng/mL, at least about 145 ng/mL, at leastabout 150 ng/mL, at least about 155 ng/mL, or at least about 158.1ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(max) on the tenth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be about 50 ng/mLto about 60 ng/mL, about 50 ng/mL to about 55 ng/mL, about 55 ng/mL toabout 60 ng/mL, about 80 ng/mL to about 90 ng/mL, about 80 ng/mL toabout 85 ng/mL, about 85 ng/mL to about 90 ng/mL, about 90 ng/mL toabout 95 ng/mL, about 95 ng/mL to about 100 ng/mL, about 100 ng/mL toabout 105 ng/mL, about 105 ng/mL to about 110 ng/mL, about 110 ng/mL toabout 115 ng/mL, about 115 ng/mL to about 120 ng/mL, about 120 ng/mL toabout 130 ng/mL, about 130 ng/mL to about 135 ng/mL, about 135 ng/mL toabout 140 ng/mL, about 140 ng/mL to about 145 ng/mL, about 145 ng/mL toabout 150 ng/mL, about 150 ng/mL to about 155 ng/mL, about 155 ng/mL toabout 160 ng/mL, about 160 ng/mL to about 170 ng/mL, about 170 ng/mL toabout 200 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, atleast about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at leastabout 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, atleast about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL,at least about 70 ng/mL, at least about 75 ng/mL, at least about 80ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at leastabout 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, atleast about 125 ng/mL, at least about 130 ng/mL, at least about 135ng/mL, at least about 140 ng/mL, at least about 145 ng/mL, at leastabout 150 ng/mL, at least about 155 ng/mL, or at least about 158.1ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered in an amount that results in a C_(avg) ofdextromethorphan, over the period between two separate and consecutiveadministrations of dextromethorphan, that is at least about 4.0 ng/mL,at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at leastabout 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, atleast about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL,at least about 40 ng/mL, at least about 45 ng/mL, at least about 50ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at leastabout 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, atleast about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at leastabout 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, atleast about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, maybe up to about 10,000 ng/mL. For example, if dextromethorphan isadministered at 8 am and at 8 pm on day 1, and no dextromethorphan isadministered after 8 am and before 8 pm on day 1, the period between twoseparate and consecutive administrations of dextromethorphan is fromimmediately after 8 am to immediately before 8 pm on day 1.

In some embodiments, the dextromethorphan C_(avg) on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at leastabout 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, atleast about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL,at least about 25 ng/mL, at least about 30 ng/mL, at least about 35ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at leastabout 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, atleast about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL,at least about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at leastabout 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, atleast about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, maybe up to about 10,000 ng/mL. The C_(avg) values given above can be forthe period between two separate and consecutive administrations ofdextromethorphan, or if dextromethorphan is administered only once onDay 8, the C_(avg) can be for 12 hours after the first dose ofdextromethorphan.

In some embodiments, the dextromethorphan C_(avg) on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at leastabout 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, atleast about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL,at least about 25 ng/mL, at least about 30 ng/mL, at least about 35ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at leastabout 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, atleast about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL,at least about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at leastabout 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, atleast about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, maybe up to about 10,000 ng/mL. The C_(avg) values given above can be forthe period between two separate and consecutive administrations ofdextromethorphan, or if dextromethorphan is administered only once onDay 9, the C_(avg) can be for 12 hours after the first dose ofdextromethorphan.

In some embodiments, the dextromethorphan C_(avg) on the tenth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, at leastabout 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, atleast about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL,at least about 25 ng/mL, at least about 30 ng/mL, at least about 35ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at leastabout 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, atleast about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL,at least about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at leastabout 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, atleast about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5ng/mL, about 20 ng/mL to about 30 ng/mL, about 30 ng/mL to about 40ng/mL, about 40 ng/mL to about 50 ng/mL, about 50 ng/mL to about 55ng/mL, about 55 ng/mL to about 60 ng/mL, about 80 ng/mL to about 90ng/mL, about 80 ng/mL to about 85 ng/mL, about 85 ng/mL to about 90ng/mL, about 90 ng/mL to about 95 ng/mL, about 95 ng/mL to about 100ng/mL, about 100 ng/mL to about 105 ng/mL, about 105 ng/mL to about 110ng/mL, about 110 ng/mL to about 115 ng/mL, about 115 ng/mL to about 120ng/mL, about 120 ng/mL to about 130 ng/mL, about 130 ng/mL to about 135ng/mL, about 135 ng/mL to about 140 ng/mL, about 140 ng/mL to about 145ng/mL, about 145 ng/mL to about 150 ng/mL, about 150 ng/mL to about 155ng/mL, about 155 ng/mL to about 160 ng/mL, about 160 ng/mL to about 170ng/mL, about 170 ng/mL to about 200 ng/mL, and, in some embodiments, maybe up to about 10,000 ng/mL. The C_(avg) values given above can be forthe period between two separate and consecutive administrations ofdextromethorphan, or if dextromethorphan is administered only once onDay 10, the C_(avg) can be for 12 hours after the first dose ofdextromethorphan.

The dextromethorphan fluctuation index values FI (%) can be determinedby equation:

${{FI}(\%)} = {\frac{( {C_{\max} - C_{\min}} )}{C_{avg}} \times 100.}$

In some embodiments, the dextromethorphan FI (%) on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is reduced by at least 1.5-fold or atleast 2-fold as compared to dextromethorphan that is administered foreight days without plasma level enhancement, such as byco-administration of dextromethorphan with of bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, the dextromethorphan FI (%) on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is reduced by at least 1.5-fold or atleast 2-fold as compared to dextromethorphan that is administered fornine days without plasma level enhancement, such as by co-administrationof dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextromethorphan FI (%) on the tenth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is reduced by at least 1.5-fold or atleast 2-fold as compared to dextromethorphan that is administered forten days without plasma level enhancement, such as by co-administrationof dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextromethorphan FI (%) on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is less than 100%, less than 50%,less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%,or any FI (%) value in a range bounded by any of these values.

In some embodiments, the dextromethorphan FI (%) on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is less than 100%, less than 50%,less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%,or any FI (%) value in a range bounded by any of these values.

In some embodiments, the dextromethorphan FI (%) on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is less than 100%, less than 50%,less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%,or any FI (%) value in a range bounded by any of these values.

In some embodiments, the dextrorphan FI (%) on the eighth day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is reduced by at least 1.5-fold, atleast 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or atleast 6-fold as compared to dextromethorphan that is administered foreight days without plasma level enhancement, such as byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextrorphan FI (%) on the ninth day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is reduced by at least 1.5-fold, atleast 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or atleast 6-fold as compared to dextromethorphan that is administered fornine days without plasma level enhancement, such as by co-administrationof dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextrorphan FI (%) on the tenth day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is reduced by at least 1.5-fold, atleast 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or atleast 6-fold as compared to dextromethorphan that is administered forten days without plasma level enhancement, such as by co-administrationof dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextrorphan FI (%) on the eighth day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is less than 100%, less than 70%,less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%,or any FI (%) value in a range bounded by any of these values.

In some embodiments, the dextrorphan FI (%) on the ninth day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is less than 100%, less than 70%,less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%,or any FI (%) value in a range bounded by any of these values.

In some embodiments, the dextrorphan FI (%) on the ninth day that thedextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is less than 100%, less than 70%,less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%,or any FI (%) value in a range bounded by any of these values.

In some embodiments, the dextromethorphan trough level (e.g. plasmalevel 12 hours after administration; also referred herein as “C_(min)”)on the first day that bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least twicethe trough level that would be achieved by administering the same amountof dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextromethorphan C_(min) on the first day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about0.8 ng/mL, at least about 0.9 ng/mL, at least about 1.0 ng/mL, at leastabout 1.1 ng/mL, at least about 1.2 ng/mL, at least about 1.3 ng/mL, atleast about 1.4 ng/mL, at least about 1.5 ng/mL, at least about 1.6ng/mL, at least about 1.7 ng/mL, at least about 1.8 ng/mL, at leastabout 1.9 ng/mL, at least about 2.0 ng/mL, at least about 2.1 ng/mL, atleast about 2.2 ng/mL, at least about 2.3 ng/mL, at least about 2.4ng/mL, at least about 2.5 ng/mL, or at least about 2.5 ng/mL, and may beup to about 100 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the fifth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at leastabout 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, atleast about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at leastabout 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, atleast about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL,at least about 65 ng/mL, at least about 70 ng/mL, at least about 75ng/mL, at least about 80 ng/mL, or at least about 80.9 ng/mL, and may beup to about 10,000 ng/m L.

In some embodiments, the dextromethorphan C_(min) on the sixth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at leastabout 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, atleast about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at leastabout 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, atleast about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL,at least about 65 ng/mL, at least about 70 ng/mL, at least about 75ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, or at leastabout 102.2 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the seventh daythat the dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at leastabout 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, atleast about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at leastabout 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, atleast about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL,at least about 65 ng/mL, at least about 70 ng/mL, at least about 75ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at leastabout 105 ng/mL, at least about 110 ng/mL, or at least about 110.6ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the eighth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at leastabout 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, atleast about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at leastabout 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, atleast about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL,at least about 65 ng/mL, at least about 70 ng/mL, at least about 75ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at leastabout 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, atleast about 119.3 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and maybe up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the ninth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at leastabout 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, atleast about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at leastabout 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, atleast about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL,at least about 65 ng/mL, at least about 70 ng/mL, at least about 75ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at leastabout 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, atleast about 119.3 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and maybe up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the tenth day thatthe dextromethorphan plasma level is enhanced, for example byco-administration of dextromethorphan with bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least about1.5 ng/mL, at least about 2.0 ng/mL, at least about 3.0 ng/mL, at leastabout 4.0 ng/mL, at least about 5.0 ng/mL, at least about 6.0 ng/mL, atleast about 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0ng/mL, at least about 10 ng/mL, at least about 15 ng/mL, at least about20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at leastabout 35 ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, atleast about 50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL,at least about 65 ng/mL, at least about 70 ng/mL, at least about 75ng/mL, at least about 80 ng/mL, at least about 85 ng/mL, at least about90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at leastabout 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, atleast about 119.3 ng/mL, about 20 ng/mL to about 30 ng/mL, about 30ng/mL to about 40 ng/mL, about 40 ng/mL to about 50 ng/mL, about 50ng/mL to about 55 ng/mL, about 55 ng/mL to about 60 ng/mL, about 80ng/mL to about 90 ng/mL, about 80 ng/mL to about 85 ng/mL, about 85ng/mL to about 90 ng/mL, about 90 ng/mL to about 95 ng/mL, about 95ng/mL to about 100 ng/mL, about 100 ng/mL to about 105 ng/mL, about 105ng/mL to about 110 ng/mL, about 110 ng/mL to about 115 ng/mL, about 115ng/mL to about 120 ng/mL, about 120 ng/mL to about 130 ng/mL, about 130ng/mL to about 135 ng/mL, about 135 ng/mL to about 140 ng/mL, about 140ng/mL to about 145 ng/mL, about 145 ng/mL to about 150 ng/mL, about 150ng/mL to about 155 ng/mL, about 155 ng/mL to about 160 ng/mL, about 160ng/mL to about 170 ng/mL, or about 170 ng/mL to about 200 ng/mL, and maybe up to about 10,000 ng/mL.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, and dextromethorphan areco-administered, as compared to the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds. For example, the dextrorphan plasma level on the first daymay be reduced by at least 5% as compared to the dextrorphan plasmalevel that would be achieved by administering the same amount ofdextromethorphan without bupropion.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, are co-administered with dextromethorphan for at least fiveconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the fifth day, the dextromethorphan plasmalevel is higher than the dextromethorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for five consecutive days. For example, the dextromethorphanplasma level on the fifth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be at least 5 times, atleast 10 times, at least 20 times, at least 40 times, at least 50 times,at least 60 times, at least 65 times, or up to about 500 times, thelevel that would be achieved by administering the same amount ofdextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for five consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least sixconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the sixth day, the dextromethorphan plasmalevel is higher than the dextromethorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for six consecutive days. For example, the dextromethorphanplasma level on the sixth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be at least 5 times, atleast 10 times, at least 20 times, at least 30 times, at least 50 times,at least 60 times, at least 70 times, at least 75 times, or up to about500 times, the level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for six consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least sevenconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the seventh day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for seven consecutive days. For example, the dextromethorphanplasma level on the seventh day (for example at 0 hours, 1 hour, 3hours, 6 hours, or 12 hours after administration) may be at least 5times, at least 10 times, at least 20 times, at least 30 times, at least50 times, at least 70 times, at least 80 times, at least 90 times, or upto about 500 times, the level that would be achieved by administeringthe same amount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for seven consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least eightconsecutive days, wherein, on the eighth day, dextromethorphan has aplasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12hours, after co-administering bupropion with dextromethorphan that is atleast 5 times, at least 10 times, at least 20 times, at least 30 times,at least 50 times, at least 60 times, at least 70 times, at least 80times, at least 90 times, at least 100 times, or up to about 1,000times, the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for eight consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan are co-administered for at least eightconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the eighth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for eight consecutive days. For example, the dextrorphanplasma level on the eighth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be reduced by at least10%, at least 20%, at least 30%, at least 40%, or at least 50%, ascompared to the dextrorphan plasma level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, for eight consecutivedays.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least nineconsecutive days, wherein, on the ninth day, dextromethorphan has aplasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12hours, after co-administering bupropion with dextromethorphan that is atleast 5 times, at least 10 times, at least 20 times, at least 30 times,at least 50 times, at least 60 times, at least 70 times, at least 80times, at least 90 times, at least 100 times, or up to about 1,000times, the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for nine consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan are co-administered for at least nineconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the ninth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for nine consecutive days. For example, the dextrorphanplasma level on the ninth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be reduced by at least10%, at least 20%, at least 30%, at least 40%, or at least 50%, ascompared to the dextrorphan plasma level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, for nine consecutivedays.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least tenconsecutive days, wherein, on the tenth day, dextromethorphan has aplasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12hours, after co-administering bupropion with dextromethorphan that is atleast 5 times, at least 10 times, at least 20 times, at least 30 times,at least 50 times, at least 60 times, at least 70 times, at least 80times, at least 90 times, at least 100 times, or up to about 1,000times, the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for ten consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan are co-administered for at least tenconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the tenth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for ten consecutive days. For example, the dextrorphan plasmalevel on the tenth day (for example at 0 hours, 1 hour, 3 hours, 6hours, or 12 hours after administration) may be reduced by at least 10%,at least 20%, at least 30%, at least 40%, or at least 50%, as comparedto the dextrorphan plasma level that would be achieved by administeringthe same amount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for ten consecutive days.

In some embodiments, bupropion may be administered to a human being inan amount that results in an AUC₀₋₃₂ of bupropion in the human being, onday 8, that is at least about 100 ng·hr/mL, at least about 200 ng·hr/mL,at least about 500 ng·hr/mL, at least about 600 ng·hr/mL, at least about700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL,at least about 1,000 ng·hr/mL, at least about 1,200 ng·hr/mL, at least1,600 ng·hr/mL, or up to about 15,000 ng·hr/mL.

In some embodiments, bupropion may be administered to a human being inan amount that results in a C_(avg) of bupropion in the human being, onday 8, that is at least about 10 ng/mL, at least about 20 ng/mL, atleast about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL,at least about 70 ng/mL, at least about 80 ng/mL, at least about 90ng/mL, at least about 100 ng/mL, at least 120 ng/mL, or up to about1,500 ng/mL.

In some embodiments, bupropion may be administered to a human being inan amount that results in a C_(max) of bupropion in the human being, onday 8, that is at least about 10 ng/mL, at least about 20 ng/mL, atleast about 50 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL,at least about 110 ng/mL, at least about 120 ng/mL, at least about 130ng/mL, at least about 140 ng/mL, at least 200 ng/mL, or up to about1,500 ng/mL.

Some liquid compositions may comprise about 0.0001% (w/v) to about 50%(w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10%(w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5%(w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15%(w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15%(w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30%(w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about50% (w/v) of bupropion, or any amount of bupropion in a range boundedby, or between, any of these values.

Some liquid dosage forms may contain about 10 mg to about 1000 mg, about50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg toabout 200 mg, about 110 mg to about 140 mg, about 180 mg to about 220mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about300 mg of bupropion, or any amount of bupropion in a range bounded by,or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), or about 80% (w/w) to about 90% (w/w) of bupropion, or any amountof bupropion in a range bounded by, or between, any of these values.

Some solid dosage forms may contain about 10 mg to about 1000 mg, about50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about70 mg to about 95 mg, about 100 mg to about 200 mg, about 100 mg toabout 120 mg, about 105 mg to about 200 mg, about 90 mg to about 120 mg,about 110 mg to about 140 mg, about 50 mg to about 150 mg, about 180 mgto about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150mg, or about 300 mg of bupropion, or any amount of bupropion in a rangebounded by, or between, any of these values.

In some embodiments, bupropion is administered at a dose that results ina bupropion plasma level of about 0.1 μM to about 10 μM, about 0.1 μM toabout 5 μM, about 0.2 μM to about 3 μM, about 0.1 μM to about 1 μM,about 0.2 μM to about 2 μM, about 1 μM to about 10 μM, about 1 μM toabout 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM,about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM toabout 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, orany plasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, is administered at a dose that results in ahydroxybupropion plasma level of about 0.1 μM to about 10 μM, about 0.1μM to about 5 μM, about 0.2 μM to about 3 μM, about 0.1 μM to about 1μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or anyplasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in an AUC₀₋₁₂ of hydroxybupropion in the human being, on day 8,that is at least about 3,000 ng·hr/mL, at least about 7,000 ng·hr/mL, atleast about 10,000 ng·hr/mL, at least about 15,000 ng·hr/mL, at leastabout 20,000 ng·hr/mL, at least about 30,000 ng·hr/mL, up to about50,000 ng·hr/mL, up to about 150,000 ng·hr/mL, or any AUC in a rangebounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in a C_(max) of hydroxybupropion in the human being, on day 8,that is at least about 300 ng/mL, at least about 700 ng/mL, at leastabout 1,000 ng/mL, at least about 1,500 ng/mL, at least about 2,000ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about50,000 ng/mL, or any C_(max) in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in a C_(avg) of hydroxybupropion in the human being, on day 8,that is at least about 200 ng/mL, at least about 300 ng/mL, at leastabout 700 ng/mL, at least about 1,000 ng/mL, at least about 1,500 ng/mL,at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about10,000 ng/mL, up to about 50,000 ng/mL, or any C_(avg) in a rangebounded by, or between, any of these values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, is administered at a dose that results in athreohydroxybupropion plasma level of about 0.1 μM to about 10 μM, about0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, about 0.1 μM to about1 μM, about 0.2 μM to about 2 μM, about 1 μM to about 10 μM, about 1 μMto about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM,about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM toabout 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, orany plasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in an AUC₀₋₁₂ of threohydroxybupropion in the human being,on day 8, that is at least about 1,000 ng·hr/mL, at least about 2,000ng·hr/mL, at least about 4,000 ng·hr/mL, at least about 5,000 ng·hr/mL,at least about 8,000 ng·hr/mL, up to about 10,000 ng·hr/mL, up to about40,000 ng·hr/mL, or any AUC in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in a C_(max) of threohydroxybupropion in the human being,on day 8, that is at least about 100 ng/mL, at least about 200 ng/mL, atleast about 400 ng/mL, at least about 500 ng/mL, at least about 600ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about10,000 ng/mL, or any C_(max) in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in a C_(avg) of threohydroxybupropion in the human being,on day 8, that is at least about 100 ng/mL, at least about 300 ng/mL, atleast about 400 ng/mL, at least about 600 ng/mL, at least about 800ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any C_(avg)in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, is administered at a dose that results in anerythrohydroxybupropion plasma level of about 0.1 μM to about 10 μM,about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, about 0.1 μM toabout 1 μM, about 0.2 μM to about 2 μM, about 1 μM to about 10 μM, about1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μMto about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM,or any plasma level in a range bounded by, or between, any of thesevalues.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in an AUC₀₋₁₂ of erythrohydroxybupropion in thehuman being, on day 8, that is at least about 200 ng·hr/mL, at leastabout 400 ng·hr/mL, at least about 700 ng·hr/mL, at least about 1,000ng·hr/mL, at least about 1,500 ng·hr/mL, at least about 3,000 ng·hr/mL,up to about 5,000 ng·hr/mL, up to about 30,000 ng·hr/mL, or any plasmalevel in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in a C_(max) of erythrohydroxybupropion in the humanbeing, on day 8, that is at least about 30 ng/mL, at least about 60ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up toabout 1,000 ng/mL, or any C_(max) in a range bounded by, or between, anyof these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in a C_(avg) of erythrohydroxybupropion in the humanbeing, on day 8, that is at least about 20 ng/mL, at least about 30ng/mL, at least about 50 ng/mL, at least about 80 ng/mL, at least about90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at leastabout 200 ng/mL, at least about 300 ng/mL, up to about 1,000 ng/mL, upto about 5,000 ng/mL, or any C_(avg) in a range bounded by, or between,any of these values.

For compositions comprising both dextromethorphan and bupropion, someliquids may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01%(w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v)to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) toabout 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) toabout 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) toabout 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) toabout 40% (w/v), about 40% (w/v) to about 50% (w/v) of dextromethorphanand bupropion combined, or any amount in a range bounded by, or between,any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), about 80% (w/w) to about 90% (w/w) of dextromethorphan andbupropion combined, or any amount in a range bounded by, or between, anyof these values.

In some embodiments, the weight ratio of dextromethorphan to bupropionin a single composition or dosage form may be about 0.1 to about 2,about 0.2 to about 1, about 0.1 to about 0.3, about 0.2 to about 0.4,about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1,about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, orany ratio in a range bounded by, or between, any of these values.

A therapeutically effective amount of a therapeutic compound may varydepending upon the circumstances. For example, a daily dose ofdextromethorphan may in some instances range from about 0.1 mg to about1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg,about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mgto about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg,about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg toabout 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg,about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg toabout 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg toabout 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg,about 240 mg, about 360 mg, or any daily dose in a range bounded by, orbetween, any of these values. Dextromethorphan may be administered oncedaily; or twice daily or every 12 hours, three times daily, four timesdaily, or six times daily in an amount that is about half, one third,one quarter, or one sixth, respectively, of the daily dose.

A daily dose of bupropion, may in some instances range from about 10 mgto about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg toabout 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about200 mg about 300 mg, about 300 mg to about 400 mg, about 400 mg to about500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg,about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600mg, or any daily dose in a range bounded by, or between, any of thesevalues. Bupropion may be administered once daily; or twice daily orevery 12 hours, or three times daily in an amount that is about half orone third, respectively, of the daily dose.

In some embodiments: 1) about 50 mg/day to about 100 mg/day, about 100mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about150 mg/day to about 200 mg/day, about 200 mg/day to about 250 mg/day,about 250 mg/day to about 300 mg/day of bupropion, or about 300 mg/dayto about 500 mg/day of bupropion; and/or 2) about 15 mg/day to about 60mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan,are administered to a human being in need thereof.

In some embodiments, about 150 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 90 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 120 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 90 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 120 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 90 mg/dayof dextromethorphan, or about 300 mg/day of bupropion and about 120mg/day of dextromethorphan is administered to the human being.

In some embodiments, about 100 mg/day of bupropion and about 15 mg/dayof dextromethorphan is administered to the human being for 1, 2, or 3days, followed by about 200 mg/day of bupropion and about 30 mg/day ofdextromethorphan. In some embodiments, about 100 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor 1, 2, or 3 days, followed by about 200 mg/day of bupropion and about60 mg/day of dextromethorphan.

In some embodiments, about 75 mg/day of bupropion and about 15 mg/day ofdextromethorphan is administered to the human being for 1, 2, or 3 days,followed by about 150 mg/day of bupropion and about 30 mg/day ofdextromethorphan. In some embodiments, about 75 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor 1, 2, or 3 days, followed by about 150 mg/day of bupropion and about60 mg/day of dextromethorphan.

An antidepressant compound, such as bupropion, may be administered foras long as needed to treat a neurological condition, such as pain,depression or cough. In some embodiments, an antidepressant compound,such as bupropion, and dextromethorphan are administered at least once aday, such as once daily or twice daily, for at least 1 day, at least 3days, at least 5 days, at least 7 days, at least 8 days, at least 9days, or at least 10 days, at least 14 days, at least 30 days, at least60 days, at least 90 days, at least 180 days, at least 365 days, orlonger.

In some embodiments, co-administration of dextromethorphan withbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a prodrug of any of these compounds, may occuronce a day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,or more days prior to co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or aprodrug of any of these compounds twice a day.

Therapeutic compounds may be formulated for oral administration, forexample, with an inert diluent or with an edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, compressed intotablets, or incorporated directly with the food of the diet. For oraltherapeutic administration, the active compound may be incorporated withan excipient and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acid,and the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose, or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present asa coating, for example, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially nontoxic inthe amounts employed.

Some compositions or dosage forms may be a liquid or may comprise asolid phase dispersed in a liquid.

Therapeutic compounds may be formulated for parental or intraperitonealadministration. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also have an oil dispersed within, or dispersed in, glycerol, liquidpolyethylene glycols, and mixtures thereof. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

SPECIFICALLY CONTEMPLATED EMBODIMENTS

The following are examples of embodiments that are specificallycontemplated by the inventor:

Embodiment 1

A method of treating pain or a neurological disorder comprisingdelivering an enhanced plasma level or bioavailability ofdextromethorphan or administering a therapeutically effective amount ofa combination of dextromethorphan and an antidepressant compound, to aperson in need thereof.

Embodiment 2

A method of treating pain comprising administering a combination of anantidepressant compound and dextromethorphan to a human being in needthereof.

Embodiment 3

A method of enhancing the pain relieving properties of dextromethorphan,comprising co-administering dextromethorphan and an antidepressantcompound.

Embodiment 4

A method of increasing dextromethorphan plasma levels in a human beingthat is an extensive metabolizer of dextromethorphan, comprisingco-administering an antidepressant compound to the human being receivinga treatment that includes administration of dextromethorphan.

Embodiment 5

A method of inhibiting the metabolism of dextromethorphan, comprisingadministering an antidepressant compound to a human being, wherein thehuman being is an extensive metabolizer of dextromethorphan, and whereindextromethorphan is present in the body of the human being at the sametime as the antidepressant compound.

Embodiment 6

A method of increasing the metabolic lifetime of dextromethorphan,comprising administering an antidepressant compound to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as the antidepressant compound.

Embodiment 7

A method of correcting extensive metabolism of dextromethorphan,comprising administering an antidepressant compound to a human being inneed thereof.

Embodiment 8

A method of improving pain relieving properties of dextromethorphancomprising administering an antidepressant compound in conjunction withadministration of dextromethorphan to a human being in need of treatmentfor pain.

Embodiment 9

A method of improving antitussive properties of dextromethorphancomprising administering an antidepressant compound in conjunction withadministration of dextromethorphan to a human being in need of treatmentfor cough.

Embodiment 10

A method of treating cough comprising administering a combination of anantidepressant compound and dextromethorphan to a human being in needthereof.

Embodiment 11

A method of improving a therapeutic property of dextromethorphancomprising administering an antidepressant compound in conjunction withadministration of dextromethorphan to a human being in need of treatmentfor a neurological disorder.

Embodiment 12

A method of treating a neurological disorder comprising administering acombination of an antidepressant compound and dextromethorphan to ahuman being in need thereof.

Embodiment 13

A method of treating a neurological disorder comprising administering anantidepressant compound and dextromethorphan to a human being in needthereof, wherein the human being is an extensive metabolizer ofdextromethorphan.

Embodiment 14

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the dextromethorphan and theantidepressant compound are administered in separate dosage forms.

Embodiment 15

A pharmaceutical composition comprising a therapeutically effectiveamount of dextromethorphan, a therapeutically effective amount of anantidepressant compound, and a pharmaceutically acceptable excipient.

Embodiment 16

An oral dosage form comprising at least 20 mg of dextromethorphan and aneffective amount of an antidepressant compound to inhibit the metabolismof dextromethorphan in a human being that is an extensive metabolizer ofdextromethorphan.

Embodiment 17

The oral dosage form of embodiment 16, wherein about 30 mg to about 350mg of dextromethorphan is present in the dosage form.

Embodiment 18

The oral dosage form of embodiment 16 or 17, wherein about 100 mg toabout 400 mg of bupropion is present in the dosage form.

Embodiment 19

The oral dosage form of any of embodiments 16, 17, or 18, comprising anamount of bupropion that results in a bupropion plasma level of about0.1 μM to about 10 μM when the oral dosage form is administered to ahuman being.

Embodiment 20

The oral dosage form of embodiment 19, comprising an amount of bupropionthat results in a bupropion plasma level of about 0.1 μM to about 2 μMwhen the oral dosage form is administered to a human being.

Embodiment 21

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein bupropion is administered at adose that results in a bupropion plasma level of about 0.1 μM to about10 μM.

Embodiment 22

The method of any preceding embodiment, such as embodiment 21, whereinbupropion is administered at a dose that results in a bupropion plasmalevel of about 0.3 μM to about 1 μM.

Embodiment 23

The method, composition, or dosage form of any preceding embodiment,such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, or 17, wherein the antidepressant compound is bupropion or ametabolite thereof.

Embodiment 24

The method, composition, or dosage form of any preceding embodiment,such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, or 17, wherein the antidepressant compound is bupropion.

Embodiment 25

The method, composition, or dosage form of any preceding embodiment,such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, or 17, wherein the antidepressant compound is clomipramine, doxepin,fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline,amoxapine, desipramine, protriptyline, trimipramine, nortriptyline,maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine,trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine,escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine,mirtazapine, nefazodone, selegiline, ketamine, or a pharmaceuticallyacceptable salt thereof

Embodiment 26

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 11, 12, 13, 14, 21, 22, 23, 24, or 25, whereindextromethorphan is administered to the human being for the treatment ofcough.

Embodiment 27

A method of treating a neurological disorder comprising administeringabout 150 mg/day to about 300 mg/day of bupropion and about 30 mg/day toabout 120 mg/day of dextromethorphan to a human being in need thereof.

Embodiment 28

A method of treating a neurological disorder comprising administeringbupropion and dextromethorphan to a human being in need thereof, whereinthe bupropion and dextromethorphan are administered at least once a dayfor at least 8 days, at least 9 days, or at least 10 days.

Embodiment 29

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, or 27,wherein bupropion is administered to the human being at least daily forat least 8 days, at least 9 days, or at least 10 days.

Embodiment 30

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, or 28,wherein dextromethorphan is administered to the human being at leastdaily for at least 8 days, at least 9 days, or at least 10 days.

Embodiment 31

The method of any preceding embodiment, such as embodiment 28, 29, or30, wherein bupropion is administered in an amount that results in aplasma concentration of dextromethorphan in the human being, on day 8,that is at least 10 times the plasma concentration of the same amount ofdextromethorphan administered without bupropion.

Embodiment 32

The method of any preceding embodiment, such as embodiment 28, 29, 30,or 31, wherein bupropion is administered in an amount that results in anAUC₀₋₁₂ of hydroxybupropion, on day 8, that is at least about 3000ng·hr/mL.

Embodiment 33

The method of any preceding embodiment, such as embodiment 28, 29, 30,31, or 32, wherein bupropion is administered in an amount that resultsin an AUC₀₋₁₂ of erythrohydroxybupropion, on day 8, that is at leastabout 400 ng·hr/mL.

Embodiment 34

The method of any preceding embodiment, such as embodiment 28, 29, 30,31, 32, or 33, wherein bupropion is administered in an amount thatresults in an AUC₀₋₁₂ of threohydroxybupropion, on day 8, that is atleast about 2000 ng·hr/mL.

Embodiment 35

The method, composition, or dosage form of any preceding embodiment,such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, or34, wherein the weight ratio of dextromethorphan to bupropion is about0.1 to about 0.5.

Embodiment 36

The method of any preceding embodiment, such as embodiment 27, 28, 29,30, 31, 32, 33, 34, or 35, wherein the human being is an extensivemetabolizer of dextromethorphan.

Embodiment 37

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human being.

Embodiment 38

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg/day of bupropion andabout 60 mg/day of dextromethorphan is administered to the human being.

Embodiment 39

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human being.

Embodiment 40

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg/day of bupropion andabout 15 mg/day of dextromethorphan is administered to the human beingfor about 1 to about 3 days, followed by about 200 mg/day of bupropionand about 30 mg/day of dextromethorphan.

Embodiment 41

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg/day of bupropion andabout 60 mg/day of dextromethorphan is administered to the human being.

Embodiment 42

The method of any preceding embodiment, such as embodiment 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor about 1 to about 3 days, followed by about 200 mg/day of bupropionand about 60 mg/day of dextromethorphan.

Embodiment 43

The method of any preceding embodiment, such as embodiment 4, 5, 6, 7,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein dextromethorphan isadministered to the human being for the treatment of pain.

Embodiment 44

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises postoperative pain, cancer pain, arthritic pain,lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain,nociceptive pain, or neuropathic pain.

Embodiment 45

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises musculoskeletal pain, neuropathic pain,cancer-related pain, acute pain, or nociceptive pain.

Embodiment 46

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises postoperative pain.

Embodiment 47

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises cancer pain.

Embodiment 48

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises arthritic pain.

Embodiment 49

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises lumbosacral pain.

Embodiment 50

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises musculoskeletal pain.

Embodiment 51

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises neuropathic pain.

Embodiment 52

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises nociceptive pain.

Embodiment 53

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises chronic musculoskeletal pain.

Embodiment 54

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with rheumatoid arthritis.

Embodiment 55

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with juvenile rheumatoid arthritis.

Embodiment 56

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with osteoarthritis.

Embodiment 57

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with an axial spondyloarthritis.

Embodiment 58

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with ankylosing spondylitis.

Embodiment 59

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with diabetic peripheral neuropathy.

Embodiment 60

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with post-herpetic neuralgia.

Embodiment 61

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with trigeminal neuralgia.

Embodiment 62

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with monoradiculopathies.

Embodiment 63

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with phantom limb pain.

Embodiment 64

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with central pain.

Embodiment 65

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises cancer-related pain.

Embodiment 66

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with lumbar nerve root compression.

Embodiment 67

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with spinal cord injury.

Embodiment 68

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with post-stroke pain.

Embodiment 69

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with central multiple sclerosis pain.

Embodiment 70

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with HIV-associated neuropathy.

Embodiment 71

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with radio-therapy associated neuropathy.

Embodiment 72

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with chemo-therapy associated neuropathy.

Embodiment 73

The method of any preceding embodiment, such as embodiment 43, whereinthe pain comprises dental pain.

Embodiment 74

The method of any preceding embodiment, such as embodiment 43, whereinthe pain is associated with primary dysmenorrhea.

Embodiment 75

The method of any preceding embodiment, such as embodiment 4, 5, 6, 7,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, or 74, wherein 90 mg/day of dextromethorphan isadministered to the human being.

Embodiment 76

The method of any preceding embodiment, such as embodiment 75, wherein45 mg of dextromethorphan is administered twice a day to the humanbeing.

Embodiment 77

The method of any preceding embodiment, such as embodiment 75 or 76,wherein 150 mg/day of bupropion is administered to the human being.

Embodiment 78

The method of any preceding embodiment, such as embodiment 75 or 76,wherein 180 mg/day of bupropion is administered to the human being.

Embodiment 79

The method of any preceding embodiment, such as embodiment 75 or 76,wherein 200 mg/day of bupropion is administered to the human being.

Embodiment 80

The method of any preceding embodiment, such as embodiment 75 or 76,wherein 300 mg/day of bupropion is administered to the human being.

Embodiment 81

A method of increasing dextromethorphan plasma levels in a human being,comprising co-administering threohydroxybupropion, hydroxybupropion,erythrohydroxybupropion, bupropion, or a prodrug thereof, withdextromethorphan to the human being, wherein the threohydroxybupropion,hydroxybupropion, erythrohydroxybupropion, bupropion, or a prodrugthereof, is administered in an amount that results in an AUC₀₋₁₂ ofdextromethorphan that is at least about 40 ng·hr/mL.

Embodiment 82

The method of any preceding embodiment, such as embodiment 81, whereinthe AUC₀₋₁₂ of dextromethorphan is at least about 50 ng·hr/mL.

Embodiment 83

The method of any preceding embodiment, such as embodiment 81 or 82,wherein the human being is in need of treatment with dextromethorphan.

Embodiment 84

The method of any preceding embodiment, such as embodiment 81, 82, or83, wherein the human being is an extensive metabolizer ofdextromethorphan.

Embodiment 85

The method of any preceding embodiment, such as embodiment 81, 82, 83,or 84, wherein the threohydroxybupropion, hydroxybupropion,erythrohydroxybupropion, bupropion, or a prodrug thereof, anddextromethorphan are administered to the human being at least daily forat least 8 days, at least 9 days, or at least 10 days.

Embodiment 86

The method of any preceding embodiment, such as embodiment 85, whereinthe AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 100 ng·hr/mL.

Embodiment 87

The method of any preceding embodiment, such as embodiment 85 or 86,wherein the AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day 10 is atleast about 400 ng·hr/mL.

Embodiment 88

The method of any preceding embodiment, such as embodiment 85, 86, or87, wherein the AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day 10is at least about 800 ng·hr/mL.

Embodiment 89

The method of any preceding embodiment, such as embodiment 85, 86, 87,or 88, wherein the AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day10 is at least about 1500 ng·hr/mL.

Embodiment 90

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, or 89, wherein the AUC₀₋₂₄ of dextromethorphan on Day 8, Day 9, orDay 10 is at least about 100 ng·hr/mL.

Embodiment 91

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, 89, or 90, wherein the AUC₀₋₂₄ of dextromethorphan on Day 8, Day 9,or Day 10 is at least about 1500 ng·hr/mL.

Embodiment 92

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, 89, 90, or 91, wherein the AUC₀₋₂₄ of dextromethorphan on Day 8, Day9, or Day 10 is at least about 2900 ng·hr/mL.

Embodiment 93

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, 89, 90, 91, or 92, wherein the AUC_(0-inf) of dextromethorphan onDay 8, Day 9, or Day 10 is at least about 100 ng·hr/m L.

Embodiment 94

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, 89, 90, 91, 92, or 93, wherein the AUC_(0-inf) of dextromethorphanon Day 8, Day 9, or Day 10 is at least about 1500 ng·hr/mL.

Embodiment 95

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, 89, 90, 91, 92, 93, or 94, wherein the AUC_(0-inf) ofdextromethorphan on Day 8, Day 9, or Day 10 is at least about 3500ng·hr/mL.

Embodiment 96

The method of any preceding embodiment, such as embodiment 85, 86, 87,88, 89, 90, 91, 92, 93, 94, or 95, wherein the AUC_(0-inf) ofdextromethorphan on Day 8, Day 9, or Day 10 is at least about 5000ng·hr/mL.

Embodiment 97

A method of increasing dextromethorphan plasma levels in a human being,comprising co-administering threohydroxybupropion, hydroxybupropion,erythrohydroxybupropion, bupropion, or a prodrug thereof, withdextromethorphan to the human being, wherein the threohydroxybupropion,hydroxybupropion, erythrohydroxybupropion, bupropion, or a prodrugthereof, is administered in an amount that results in a C_(max) ofdextromethorphan that is at least about 6 ng/mL.

Embodiment 98

The method of any preceding embodiment, such as embodiment 97, whereinthe human being is in need of treatment with dextromethorphan.

Embodiment 99

The method of any preceding embodiment, such as embodiment 97 or 98,wherein the human being is an extensive metabolizer of dextromethorphan.

Embodiment 100

The method of any preceding embodiment, such as embodiment 97, 98, or99, wherein the threohydroxybupropion, hydroxybupropion,erythrohydroxybupropion, bupropion, or a prodrug thereof, anddextromethorphan are administered to the human being at least daily forat least 8 days, at least 9 days, or at least 10 days.

Embodiment 101

The method of any preceding embodiment, such as embodiment 100, whereinthe C_(max) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 20 ng/mL.

Embodiment 102

The method of any preceding embodiment, such as embodiment 100 or 101,wherein the C_(max) of dextromethorphan on Day 8, Day 9, or Day 10 is atleast about 60 ng/mL.

Embodiment 103

The method of any preceding embodiment, such as embodiment 100, 101, or102, wherein the C_(max) of dextromethorphan on Day 8, Day 9, or Day 10is at least about 120 ng/m L.

Embodiment 104

A method of increasing dextromethorphan plasma levels in a human being,comprising co-administering threohydroxybupropion, hydroxybupropion,erythrohydroxybupropion, bupropion, or a prodrug thereof, withdextromethorphan to the human being, wherein the threohydroxybupropion,hydroxybupropion, erythrohydroxybupropion, bupropion, or a prodrugthereof, is administered in an amount that results in a C_(avg) ofdextromethorphan over a 12 hour period, after one administration, thatis at least about 5 ng/mL.

Embodiment 105

The method of any preceding embodiment, such as embodiment 104, whereinthe human being is in need of treatment with dextromethorphan.

Embodiment 106

The method of any preceding embodiment, such as embodiment 104 or 105,wherein the human being is an extensive metabolizer of dextromethorphan.

Embodiment 107

The method of any preceding embodiment, such as embodiment 104, 105, or106, wherein the threohydroxybupropion, hydroxybupropion,erythrohydroxybupropion, bupropion, or a prodrug thereof, anddextromethorphan are administered to the human being at least daily forat least 8 days, at least 9 days, or at least 10 days.

Embodiment 108

The method of any preceding embodiment, such as embodiment 107, whereinthe C_(avg) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 20 ng/mL.

Embodiment 109

The method of any preceding embodiment, such as embodiment 107 or 108,wherein the C_(avg) of dextromethorphan on Day 8, Day 9, or Day 10 is atleast about 70 ng/mL.

Embodiment 110

The method of any preceding embodiment, such as embodiment 107, 108, or109, wherein the C_(avg) of dextromethorphan on Day 8, Day 9, or Day 10is at least about 120 ng/m L.

Embodiment 111

A method of increasing dextromethorphan plasma levels in a human being,comprising co-administering bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any ofthese compounds, with dextromethorphan to the human being, wherein thebupropion or a prodrug thereof is administered in an amount that resultsin an AUC₀₋₁₂ of dextromethorphan that is at least about 40 ng·hr/mL.

Embodiment 112

The method of any preceding embodiment, such as embodiment 111, whereinthe AUC₀₋₁₂ of dextromethorphan is at least about 50 ng·hr/mL.

Embodiment 113

The method of any preceding embodiment, such as embodiment 111 or 112,wherein the human being is in need of treatment with dextromethorphan.

Embodiment 114

The method of any preceding embodiment, such as embodiment 111, 112, or113, wherein the human being is an extensive metabolizer ofdextromethorphan.

Embodiment 115

The method of any preceding embodiment, such as embodiment 111, 112,113, or 114, wherein the bupropion or a prodrug thereof isco-administered with dextromethorphan at least daily for at least twoconsecutive days.

Embodiment 116

The method of any preceding embodiment, such as embodiment 115, whereinthe bupropion or a prodrug thereof and dextromethorphan are administeredto the human being at least daily for at least 8 days, at least 9 days,or at least 10 days.

Embodiment 117

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 100 ng·hr/mL.

Embodiment 118

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 800 ng·hr/mL.

Embodiment 119

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC₀₋₁₂ of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 1500 ng·hr/mL.

Embodiment 120

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC₀₋₂₄ of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 100 ng·hr/mL.

Embodiment 121

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC₀₋₂₄ of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 1500 ng·hr/mL.

Embodiment 122

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC_(0-inf) of dextromethorphan on Day 8, Day 9, or Day 10 is atleast about 100 ng·hr/mL.

Embodiment 123

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC_(0-inf) of dextromethorphan on Day 8, Day 9, or Day 10 is atleast about 3500 ng·hr/mL.

Embodiment 124

The method of any preceding embodiment, such as embodiment 116, whereinthe AUC_(0-inf) of dextromethorphan on Day 8, Day 9, or Day 10 is atleast about 5000 ng·hr/mL.

Embodiment 125

A method of increasing dextromethorphan plasma levels in a human being,comprising co-administering bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any ofthese compounds, with dextromethorphan to the human being, wherein thebupropion or a prodrug thereof is administered in an amount that resultsin a C_(max) of dextromethorphan that is at least about 6 ng/mL.

Embodiment 126

The method of any preceding embodiment, such as embodiment 125, whereinthe human being is in need of treatment with dextromethorphan.

Embodiment 127

The method of any preceding embodiment, such as embodiment 125 or 126,wherein the human being is an extensive metabolizer of dextromethorphan.

Embodiment 128

The method of any preceding embodiment, such as embodiment 126, 127, or128, wherein the bupropion or a prodrug thereof is co-administered withdextromethorphan at least daily for at least two consecutive days.

Embodiment 129

The method of any preceding embodiment, such as embodiment 128, whereinthe bupropion or a prodrug thereof and dextromethorphan are administeredto the human being at least daily for at least 8 days, at least 9 days,or at least 10 days.

Embodiment 130

The method of any preceding embodiment, such as embodiment 129, whereinthe C_(max) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 10 ng/mL.

Embodiment 131

The method of any preceding embodiment, such as embodiment 129, whereinthe C_(max) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 60 ng/mL.

Embodiment 132

The method of any preceding embodiment, such as embodiment 129, whereinthe C_(max) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 120 ng/mL.

Embodiment 133

A method of increasing dextromethorphan plasma levels in a human being,comprising co-administering bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any ofthese compounds, with dextromethorphan to the human being, wherein thebupropion or a prodrug thereof is administered in an amount that resultsin a C_(avg) of dextromethorphan, over the period between two separateand consecutive administrations of dextromethorphan, that is at leastabout 5 ng/mL.

Embodiment 134

The method of any preceding embodiment, such as embodiment 134, whereinthe bupropion or a prodrug thereof is administered in an amount thatresults in a C_(avg) of dextromethorphan, over the period between twoseparate and consecutive administrations of dextromethorphan, that is atleast about 60 ng/mL.

Embodiment 135

The method of any preceding embodiment, such as embodiment 134, whereinthe human being is in need of treatment with dextromethorphan.

Embodiment 136

The method of any preceding embodiment, such as embodiment 134 or 135,wherein the human being is an extensive metabolizer of dextromethorphan.

Embodiment 137

The method of any preceding embodiment, such as embodiment 134, 135, or136, wherein the bupropion or a prodrug thereof is co-administered withdextromethorphan at least daily for at least two consecutive days.

Embodiment 138

The method of any preceding embodiment, such as embodiment 137, whereinthe bupropion or a prodrug thereof and dextromethorphan are administeredto the human being at least daily for at least 8 days, at least 9 days,or at least 10 days.

Embodiment 139

The method of any preceding embodiment, such as embodiment 138, whereinthe C_(avg) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 8 ng/mL, wherein the C_(avg) is for the period between twoseparate and consecutive administrations of dextromethorphan, or ifdextromethorphan is administered only once on Day 8, Day 9, or Day 10,the C_(avg) is for 12 hours after the first dose of dextromethorphan onDay 8, Day 9, or Day 10.

Embodiment 140

The method of any preceding embodiment, such as embodiment 138, whereinthe C_(avg) of dextromethorphan on Day 8, Day 9, or Day 10 is at leastabout 120 ng/mL, wherein the C_(avg) is for the period between twoseparate and consecutive administrations of dextromethorphan, or ifdextromethorphan is administered only once on Day 8, Day 9, or Day 10,the C_(avg) for 12 hours after the first dose of dextromethorphan on Day8, Day 9, or Day 10.

Embodiment 141

A method of improving the efficacy of bupropion in treating depression,comprising: orally administering about 90 mg to about 125 mg of abupropion in combination with about 0.3 mg/kg to about 1 mg/kg of adextromethorphan, once or twice a day for at least 23 days, to a humanbeing suffering from depression, wherein orally administering thebupropion in combination with the dextromethorphan is more effective intreating depression than orally administering the same dosage regimen ofbupropion without dextromethorphan.

Embodiment 142

The method of embodiment 141, wherein about 0.6 mg/kg to about 0.8 mg/kgof the dextromethorphan is orally administered once or twice a day.

Embodiment 143

The method of embodiment 141, wherein about 45 mg of thedextromethorphan is orally administered once or twice a day.

Embodiment 144

The method of embodiment 141, wherein about 100 mg to about 120 mg ofthe bupropion is orally administered once or twice a day.

Embodiment 145

The method of embodiment 142, wherein about 105 mg of the bupropion isorally administered once or twice a day.

Embodiment 146

The method of embodiment 141, wherein the dextromethorphan and thebupropion are orally administered for at least 35 days.

Embodiment 147

The method of embodiment 141, wherein the human being is suffering fromtreatment-resistant depression.

Embodiment 148

The method of embodiment 141, wherein the dextromethorphan is orallyadministered in a dosage form that provides immediate release of thedextromethorphan.

Embodiment 149

The method of embodiment 143, wherein the dextromethorphan is orallyadministered in a dosage form that provides immediate release of thedextromethorphan.

Embodiment 150

The method of embodiment 141, wherein the bupropion is orallyadministered in a dosage form that provides sustained release of thebupropion.

Embodiment 151

The method of embodiment 145, wherein the bupropion is orallyadministered in a dosage form that provides sustained release of thebupropion.

Embodiment 152

The method of embodiment 150, wherein about 105 mg of the bupropion isorally administered once or twice a day in a dosage form that providessustained release of the bupropion.

Embodiment 153

The method of embodiment 152, wherein the bupropion and thedextromethorphan are orally administered together in a single dosageform that is orally administered once or twice a day.

Embodiment 154

The method of embodiment 153, wherein the dextromethorphan and thebupropion are orally administered for at least 5 weeks.

Embodiment 155

The method of embodiment 141, wherein the human being is suffering frommajor depressive disorder.

Embodiment 156

The method of embodiment 154, wherein the bupropion comprises anenantiomeric excess of an R-enantiomer.

Embodiment 157

The method of embodiment 154, wherein the bupropion comprises anenantiomeric excess of an S-enantiomer.

Embodiment 158

The method of embodiment 141, wherein the dextromethorphan comprises adeuterium-modified dextromethorphan.

Embodiment 159

The method of embodiment 141, wherein the human being is currentlysuffering from depression and has previously been unsuccessfully treatedwith at least two antidepressants.

Embodiment 160

A method of treating treatment-resistant depression comprising:

selecting a human being suffering from depression who has previouslybeen unsuccessfully treated with at least one antidepressant; and

orally administering a dextromethorphan-bupropion combination treatmentonce or twice a day to the human being for at least about five weeks;

wherein the dextromethorphan-bupropion combination treatment comprisesabout 40 mg to about 70 mg of a dextromethorphan and about 100 mg toabout 140 mg of a bupropion.

Embodiment 161

The method of embodiment 160, wherein the bupropion comprises anenantiomeric excess of an enantiomer.

Embodiment 162

The method of embodiment 160, wherein the dextromethorphan comprises adeuterium-modified dextromethorphan.

Embodiment 163

The method of embodiment 160, wherein the dextromethorphan-bupropioncombination treatment comprises about 40 mg to about 50 mg of thedextromethorphan.

Embodiment 164

The method of embodiment 160, wherein the dextromethorphan-bupropioncombination treatment comprises about 100 mg to about 110 mg of thebupropion.

Embodiment 165

The method of embodiment 163, wherein the dextromethorphan-bupropioncombination treatment comprises about 100 mg to about 110 mg of thebupropion.

Embodiment 166

The method of embodiment 165, wherein the dextromethorphan and thebupropion are orally administered in a single dosage form that providesimmediate release for the dextromethorphan and sustained release for thebupropion.

Embodiment 167

The method of embodiment 166, further comprising orally administeringthe dextromethorphan-bupropion combination treatment once a day forabout 1, 2, 3, 4, 5, 6, or 7 days prior to orally administering thedextromethorphan-bupropion combination treatment twice a day to thehuman being for at least about five weeks.

Embodiment 168

The method of embodiment 167, wherein the dextromethorphan-bupropioncombination treatment comprises about 45 mg of the dextromethorphan.

Embodiment 169

The method of embodiment 168, wherein the dextromethorphan-bupropioncombination treatment comprises about 105 mg of the bupropion.

Embodiment 170

The method of embodiment 160, wherein the antidepressant is duloxetine.

EXAMPLES Example 1

Fifteen human subjects were randomized into one of two treatment groupsreceiving either dextromethorphan (DM) alone, or DM in combination withbupropion, as shown in Table 1 below.

TABLE 1 Study Design Dose Levels Bupropion/ Total Group DM DosingRegimen Duration Subjects A 0 mg/60 mg DM: Twice daily, Days 1-8 Days1-8 8 B 150 mg/ Bupropion: Once daily, Days 1-8 7 60 mg Days 1-3; Twicedaily, Days 4-8 DM: Twice daily, Days 1-8

All subjects were extensive, including ultra-rapid, metabolizers ofdextromethorphan as determined by CYP2D6 genetic testing.Dextromethorphan was dosed at 12-hour intervals on Days 1-8, with afinal morning dose on Day 8. Bupropion was dosed once daily on Days 1-3,and at 12-hour intervals thereafter, with a final morning dose on Day 8.

Plasma samples were collected for concentration analysis ofdextromethorphan, total dextrorphan, bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8.Plasma samples for determination of trough concentrations ofdextromethorphan were obtained approximately 12 hours after dosing ondays 1, 5, 6, and 8.

Concentrations of dextromethorphan, total dextrorphan (unconjugated andglucuronide forms), bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion, were determinedusing LC-MS/MS. Pharmacokinetic parameters were calculated.

Phenotypic determination of dextromethorphan metabolizer status wasperformed by calculating the dextromethorphan/dextrorphan metabolicratio as described in Jurica et al. Journal of Clinical Pharmacy andTherapeutics, 2012, 37, 486-490. Plasma concentrations ofdextromethorphan and dextrorphan 3 hours after dosing were used, with adextromethorphan/dextrorphan ratio of 0.3 or greater indicating a poormetabolizer phenotype.

Results

Plasma concentrations of dextromethorphan were significantly increasedwith bupropion administration, as illustrated in FIG. 1 and Table 2.

TABLE 2 Mean Day 8 Dextromethorphan Plasma Concentrations (ng/mL)Dextromethorphan + Time Dextromethorphan Bupropion (hours) (Group A)(Group B) 0 1.2 110.6 1 2.4 129.3 2 3.6 153.9 3 3.6 151.6 4 3.3 149.1 62.5 150.0 8 1.9 144.4 12 1.1 119.3 24 0.4 95.3 36 0.1 69.0

The AUC of dextromethorphan was significantly increased withadministration of bupropion as show in FIGS. 2-4. As shown in FIG. 5 andTable 2A, administration of bupropion with dextromethorphan resulted inan approximately 60-fold, 80-fold, and 175-fold increase in meandextromethorphan AUC₀₋₁₂, AUC₀₋₂₄, and AUC_(0-inf), respectively on Day8 as compared to administration of dextromethorphan alone. As shown inFIG. 6 and Table 2B, the increase in dextromethorphan AUC occurred asearly as Day 1 (an approximate 3-fold increase in AUC₀₋₁₂).

TABLE 2A Day 8 Values Dextromethorphan + Dextromethorphan Bupropion(Group (Group A) B) AUC₀₋₁₂ (ng * hr/mL) 28.1 1,686.3 AUC₀₋₂₄ (ng *hr/mL) 37.1 2,975.3 AUC_(0-inf) 41.2 7,237.3 (ng * hr/mL) C_(max)(ng/mL) 3.8 158.1 C_(min) (ng/mL) 1.1 119.3 C_(avg) (ng/mL) 2.3 140.5

TABLE 2B Day 1 Values Dextromethorphan + Dextromethorphan Bupropion(Group (Group A) B) AUC₀₋₁₂ 20.1 56.5 (ng * hr/mL) C_(max) (ng/mL) 3.08.7

Trough plasma concentrations (also referred to as “minimum mean plasmaconcentrations” or “C_(min)”) of dextromethorphan were significantlyincreased with administration of bupropion as illustrated in FIG. 7 andTables 2A and 3. Administration of bupropion with dextromethorphanresulted in an approximately 105-fold increase in mean trough plasmaconcentration of dextromethorphan on Day 8 as compared to administrationof dextromethorphan alone.

Mean average plasma concentrations (C_(avg)) of dextromethorphan on Day8 increased approximately 60-fold with bupropion administration ascompared to administration of dextromethorphan alone, as illustrated inTable 2A. Maximum mean plasma concentrations (C_(max)) were alsosignificantly increased as illustrated in FIG. 8 and Table 2A.

TABLE 3 Mean Trough Dextromethorphan Plasma Concentrations (ng/mL)Dextromethorphan + Dextromethorphan Bupropion Fold (Group A) (Group B)Change Day 1 0.7 2.5 3.5 Day 5 1.2 80.9 70 Day 6 1.3 102.2 78 Day 7 1.2110.6 94 Day 8 1.1 119.3 105

The T_(max) and elimination half-life (T_(1/2 el)) of dextromethorphanwere significantly increased with administration of bupropion on Day 8.The increase of T_(1/2 el) shows that the metabolic lifetime ofdextromethorphan was increased. Administration of bupropion withdextromethorphan resulted in a mean T_(max) of 3.6 hours, compared to2.3 hours for dextromethorphan alone. Administration of bupropion withdextromethorphan resulted in a mean T_(1/2 el) of 27.7 hours, comparedto 6.6 hours for dextromethorphan alone.

Plasma concentrations of dextrorphan were significantly decreased withbupropion administration, as illustrated in FIG. 9 and Table 4.

TABLE 4 Mean Day 8 Dextrorphan Plasma Concentrations (ng/mL)Dextromethorphan + Time Dextromethorphan Bupropion (hours) (Group A)(Group B) 0 132.4 165.3 1 688.9 190.7 2 959.1 214.9 3 778.1 214.4 4594.9 205.1 6 324.7 172.5 8 189.6 159.6 12 74.8 152.8 24 12.2 133.0 360.1 107.6

As shown in FIGS. 10-11, there was an approximate 78% reduction in meandextrorphan C_(max), and an approximate 55% reduction in meandextrorphan AUC₀₋₁₂ on Day 8 with administration of bupropion.

Phenotypic determination of dextromethorphan metabolizer status showedthat no subjects in either treatment arm were poor metabolizers onDay 1. On Day 8 however, 100% of subjects treated with bupropion hadconverted to poor metabolizer status as compared to 0% of subjectstreated with dextromethorphan alone. The mean plasmadextromethorphan/dextrorphan metabolic ratio increased from 0.01 on Day1 to 0.71 on Day 8 with bupropion administration. The mean ratio in thegroup administered DM alone was 0.00 on Day 1 and remained unchanged onDay 8.

On Day 8, average plasma concentrations of bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion were at least 10ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively after bupropionadministration.

As used in this section, the term “fold change” or “fold increase”refers to the ratio of a value for bupropion with dextromethorphan tothe same value for dextromethorphan alone (i.e. the value for bupropionwith dextromethorphan divided by the same value for dextromethorphanalone).

Example 2

The ability of various antidepressant compounds to inhibit themetabolism of dextromethorphan was examined using human livermicrosomes. Each antidepressant compound was incubated at sevenincreasing concentrations (0.1-100 μM) in duplicate with human livermicrosomes (0.5 mg/mL) in the presence of dextromethorphan (5 μM) at 37°C. The assay was performed in the presence of 2 mM NADPH in 100 mMpotassium phosphate (pH 7.4) containing 5 mM magnesium chloride, in a200 μL assay final volume.

After optimal incubation at 37° C., the reactions were terminated byaddition of methanol containing internal standard for analyticalquantification. The quenched samples were incubated at 4° C. for 10minutes and centrifuged at 4° C. for 10 minutes. The supernatant wasremoved and the metabolite of dextromethorphan (dextrorphan) wasanalyzed by LC-MS/MS. A decrease in the formation of the metabolitecompared to vehicle control was used to calculate an ICso value (thetest concentration which produces 50% inhibition of dextromethorphanmetabolism) for each antidepressant compound, with a lower ICsoindicating greater potency.

The results are summarized in Table 5 below, and the correspondingpotencies are depicted in FIG. 12.

TABLE 5 Potency of Various Antidepressant Compounds for Inhibition ofthe Metabolism of Dextromethorphan in Human Liver Microsomes TestCompound Mean IC₅₀ (μM) Desvenlafaxine 97.3 Venlafaxine 27.7Escitalopram 17.1 Citalopram 14.1 (2S,3S)-Hydroxybupropion 12.5Bupropion 9.1 (R,R)-Hydroxybupropion 8.2 Fluvoxamine 6.5 Sertraline 5.1(S)-Duloxetine 4.1 Threohydroxybupropion 3.9 Erythrohydroxybupropion 1.4

Example 3

Phase 2 Clinical Trial Design:

The Phase 2 clinical trial with the administration of a combination ofdextromethorphan and bupropion (DM/BU) was a randomized, double-blind,active-controlled, multi-center, U.S. trial with 80 adult patients withconfirmed diagnosis of moderate to severe major depressive disorder(MDD), who received a twice daily dose for a 6-week treatment period.Dose groups (1:1 randomization) included DM/BU (45 mgdextromethorphan/105 mg bupropion) with 43 patients, or activecomparator bupropion (105 mg) with 37 patients. Among these patients,23% of them had received prior first line treatment for depression. Theclinical trial had extensive quality control measures.

The Primary Endpoint:

The changes from baseline in the Montgomery-AsbergDepression RatingScale (MADRS) total score over the 6-week treatment period werecalculated at each time point and averaged.

FIG. 13 and Table A shows the changes in MADRS total score over the timeduring the 6-week dosing period for the subjects administered bupropion(BU) or the combination of dextromethorphan and bupropion (DM/BU).

TABLE A Primary Endpoint DM + BU BU P-Value Change in MADRS Total Scoreover −13.7 −8.8 <0.001 6-week period (averaged) Change in MADRS TotalScore at week 6 −17.2 −12.1 0.013

The Secondary Endpoints:

Table B listed the secondary endpoints with P-values.

TABLE B Secondary Endpoint P-Value* MADRS Total Score Change Weeks 1-20.01 % Achieving Remission on MADRS at Week 2 0.004 % AchievingRemission on MADRS at Week 6 0.004 MADRS-6 Change at Week 6 0.007 % ofResponders on MADRS-6 (≥50% 0.014 reduction from baseline) at Week 6Clinical Global Impression-Improvement (CGI-I) at Week 1 0.045 CGI-I atWeek 6 0.051 Clinical Global Impression-Severity (CGI-S) at Week 6 0.028*P-values are for DM/BU versus active comparator bupropion (BU).Multiple secondary endpoints favored DM/BU.

FIG. 14 shows the percent of subjects achieving remission (as determinedby MADRS 10) over the time during the 6-week dosing period for thesubjects administered bupropion (BU) or the combination ofdextromethorphan and bupropion (DM/BU).

Safety:

The clinical study showed that the administration of the DM/BU was safeand well tolerated with similar rates of adverse events in the DM/BU andbupropion arms. No serious adverse events were observed. There was nomeaningful difference between the two treatment arms in discontinuationsdue to adverse events. The most commonly reported adverse events in theDM/BU arm were nausea, dizziness, dry mouth, decreased appetite, andanxiety. The DM/BU was not associated with psychotomimetic effects,weight gain, or increased sexual dysfunction.

SUMMARY

Statistically significant improvements on MADRS and secondary efficacyendpoints for DM/BU in patients with MDD were achieved. Early andsustained separation from active comparator bupropion were observed. Theadministration of DM/BU was safe and well-tolerated with nopsychotomimetic effects, weight gain, or increased sexual dysfunction

Thus, DM/BU demonstrated significant and rapid antidepressant activitywith a favorable safety profile in the clinical trial in MDD.

Results:

FIGS. 13 and 14 are prepared based on the results of the US clinicaltrials with 80 adult patients having depression with 43 patients treatedwith the combination of 45 mg of DM and 105 mg of BU, and 37 patientstreated with 105 mg of BU alone who received a twice daily dose for the6-week treatment period. Among these patients, 23% of them had receivedprior first line treatment for depression.

As shown in FIG. 13 and Table A, the MADRS total score (depressionrating scale) was significantly reduced with the combination of DM andBU than that of BU alone even at the first week of the treatment. Atweek 6, administration of the combination DM/BU reduced the MADRS totalscore by about 42% as compared to bupropion alone.

As shown in FIG. 14, even in as early as the second week of thetreatment, the remission rate for the combination of DM/BU issignificantly higher than that for the comparator BU alone (about 8times) with about 20% higher remission rate. At week 6 of the treatment,the administration of combination DM/BU resulted in about 30% higherremission rate than that of the comparator BU alone.

The above clinical study showed that the administration of thecombination of bupropion with dextromethorphan (DM/BU) provides greaterefficacy than would otherwise be achieved by administering bupropionalone. This clinical study demonstrated that the combination ofdextromethorphan and bupropion has an additive or synergistic efficacyin treating depression.

Example 4: Product Kit

In some embodiments, a product kit comprises a combination ofdextromethorphan and bupropion, for treating depression, wherein theproduct kit contains a dosage form containing about 30 mg to about 60 mgof dextromethorphan and about 100 mg to about 200 mg of bupropion, andwherein administration of the dosage form once daily or twice dailyresults in greater efficacy in the human being than that foradministering bupropion alone. In some embodiments, the product kitcontains 45 mg of dextromethorphan and 105 mg of bupropion.

In some embodiments, a product kit comprises an oral sustained releasedelivery system for dextromethorphan, comprising bupropion;dextromethorphan; and a water soluble vehicle in a dosage form, whereinthe dosage form contains about 30 mg to about 60 mg of dextromethorphanand about 100 mg to about 200 mg of bupropion, and wherein the use ofthe dosage form once or twice daily for at least eight days results inthe increase of elimination half-life (T_(1/2)) of dextromethorphan thanthat for administration dextromethorphan alone on the eighth day.

Example 5

Nearly 40 million American adults smoke and around 70% of them reportthat they want to quit. Tobacco use results in approximately 500,000premature deaths each year in the U.S. alone, according to the Centersfor Disease Control and Prevention. Smoking is the single largest causeof premature deaths worldwide accounting for an estimated almost 20% ofall deaths in developed countries [Dani J A and Heinemann S (1996)Neuron 16:5, pp. 905-8]. Direct health care and lost productivity costsas a result of smoking total nearly $300 billion a year in the U.S.alone. It is estimated that only 3 to 5% of cigarette smokers whoattempt to quit without assistance are successful for 6-12 months, andthe relapse rate remains above 80% even with current treatments [HughesJ R, et al. (2004) Addiction 99:1, pp. 29-38]. As the vast majority ofsmokers who attempt to quit fail to do so highlighting the need for newapproaches. The combination of dextromethorphan and bupropion (DM/BU)has the potential to address this condition due to the novel mechanismsof action of DM/BU.

The combination of dextromethorphan and bupropion (DM/BU) is a novel,oral, investigational NMDA receptor antagonist with multimodal activityunder development for the treatment of central nervous system (CNS)disorders. The dextromethorphan component of DM/BU is a non-competitiveN-methyl-D-aspartate (NMDA) receptor antagonist, also known as aglutamate receptor modulator, which is a novel mechanism of action thatworks differently than currently available therapies for depression. Thedextromethorphan component of DM/BU is also a sigma-1 receptor agonist,nicotinic acetylcholine receptor antagonist, and inhibitor of theserotonin and norepinephrine transporters. The bupropion component ofDM/BU serves to increase the bioavailability of dextromethorphan, and isa norepinephrine and dopamine reuptake inhibitor, and a nicotinicacetylcholine receptor antagonist. Both components of DM/BU arenicotinic acetylcholine receptor antagonists, a mechanism that isrelevant to nicotine dependence. Thus, DM/BU provides a potentially newmechanism of action for smoking cessation treatment.

Phase 2 Clinical Trial Design:

The clinical trial was a Phase 2, randomized, double-blind,active-controlled study to evaluate the efficacy and safety of DM/BU forsmoking cessation treatment. A total of 58 smokers were randomized in a1:1 ratio to receive either DM/BU (45 mg dextromethorphan/105 mgbupropion) (n=31), or the active comparator bupropion (105 mg) (n=27),twice daily, and assessed over a 3-week period. Enrolled subjects weredaily smokers using 10 or more cigarettes per day. The average number ofcigarettes smoked per day at baseline was 20 for DM/BU and 17 for thebupropion treatment groups.

The Primary Endpoint:

The primary outcome measure was the change in smoking intensity,measured using the number of cigarettes smoked per day, assessed viadaily smoking diaries.

Safety:

Medication adherence was similar between the study arms for both themorning dose (97.1% for DM/BU and 96.6% for bupropion) and the eveningdose (76.3% for DM/BU and 79.4% for bupropion). In the study, DM/BU wassafe and well tolerated with no serious adverse events. The mostcommonly reported side effects were headache, dry mouth, andinsomnia/vivid dreams, with similar incidences in both treatment arms.

Results:

Treatment with DM/BU resulted in a 25% greater reduction in the averagenumber of cigarettes smoked per day over the 3-week period, theprespecified primary endpoint, as compared to bupropion (averagereductions of 8.49 and 6.79 cigarettes per day for DM/BU and bupropion,respectively, p=0.0016).

Consistent with this finding, a greater proportion of smokers receivingDM/BU experienced a more than 50% reduction in expired carbon monoxidelevels, a biochemical marker of smoking intensity, as compared to thosetreated with bupropion (52.0% for DM/BU versus 30.4% for bupropion,p=0.15).

In addition, the human subjects who took DM/BU as prescribed on a givenday smoked 1.0 fewer cigarette on the day of medication use of DM/BU(p=0.026) and 1.2 fewer cigarettes on the following day (p=0.008) ascompared to those who missed one or both doses of DM/BU.

SUMMARY

The treatment with DM/BU achieves the prespecified primary endpoint inPhase 2 Trial in Smoking Cessation. The treatment with DM/BUdemonstratedstatistically significant reduction in daily smoking compared to theactive comparator bupropion alone (p=0.0016). The findings in this phase2 clinical trial are notable because DM/BU was compared to bupropion,which is an approved treatment for smoking cessation.

Furthermore, it is worth noting that the improvement of DM/BU overbupropion observed in this clinical trial in human beings is similar inmagnitude to the improvement over placebo reported for the approvedsmoking cessation treatment varenicline in studies with a similardesign. Varenicline is a prescription medication used to treat smokingaddiction. This medication is the first approved nicotinic receptorpartial agonist. Specifically, varenicline is a partial agonist of thealpha4/beta2 subtype of the nicotinic acetylcholine receptor.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, percentage, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the embodiments (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theembodiments and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or to expedite prosecution. When any suchinclusion or deletion occurs, the specification is deemed to contain thegroup as modified thus fulfilling the written description of all Markushgroups if used in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the claimed embodiments. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the claimed embodiments to bepracticed otherwise than specifically described herein. Accordingly, theclaims include all modifications and equivalents of the subject matterrecited in the claims as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is contemplated unless otherwise indicated herein or otherwiseclearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

What is claimed is:
 1. A method of using dextromethorphan with enhancedplasma levels to treat a human being, wherein the human being is anextensive metabolizer of the dextromethorphan and suffers fromtreatment-resistant depression, comprising orally administering a dosageform comprising about 200 mg to about 300 mg of bupropion and about 80mg to about 130 mg of the dextromethorphan to the human being, whereinthe dosage form is administered once a day for at least eightconsecutive days, and the method results in a first C_(min) of thedextromethorphan that is at least about 20 ng/mL on the eighth day, andwherein the first C_(min) of the dextromethorphan is at least about 20times a second C_(min) of the dextromethorphan that would result fromadministering the same amount of the dextromethorphan without thebupropion to the human being twice a day for eight consecutive days. 2.The method of claim 1, wherein about 80 mg to about 100 mg of thedextromethorphan is orally administered once daily.
 3. The method ofclaim 1, wherein the weight ratio of dextromethorphan to bupropion inthe dosage form is about 0.2 to about 0.4.
 4. The method of claim 1,wherein the weight ratio of dextromethorphan to bupropion in the dosageform is about 0.3 to about 0.5.
 5. The method of claim 1, wherein theweight ratio of dextromethorphan to bupropion in the dosage form isabout 0.5 to about 0.7.
 6. The method of claim 1, wherein the firstC_(min) of the dextromethorphan is at least about 30 times the secondC_(min) of the dextromethorphan.
 7. The method of claim 1, wherein thefirst C_(min) of the dextromethorphan is at least about 40 times thesecond C_(min) of the dextromethorphan.
 8. The method of claim 1,wherein the first C_(min) of the dextromethorphan is at least about 50times the second C_(min) of the dextromethorphan.
 9. The method of claim1, wherein the first C_(min) of the dextromethorphan is at least about30 ng/m L.
 10. The method of claim 1, wherein the first C_(min) of thedextromethorphan is least about 50 ng/m L.
 11. The method of claim 1,wherein about 200 mg of the bupropion is orally administered once daily.12. The method of claim 1, wherein about 200 mg to about 250 mg of thebupropion is orally administered once daily.
 13. The method of claim 1,wherein about 250 mg to about 300 mg of the bupropion is orallyadministered once daily.
 14. The method of claim 1, wherein thebupropion is deuterium-modified.
 15. The method of claim 1, wherein thedextromethorphan is deuterium-modified.
 16. The method of claim 1,wherein the dosage form is a solid.
 17. The method of claim 1, whereinthe dosage form further comprises a binder.
 18. The method of claim 1,wherein the dosage form further comprises a disintegrating agent. 19.The method of claim 1, wherein the dosage form further comprises alubricant.
 20. The method of claim 1, wherein the dosage form is atablet, a troche, a pill or a capsule.
 21. The method of claim 1,wherein the dosage form is orally administered once a day for at least30 consecutive days.
 22. The method of claim 1, wherein the dosage formis orally administered once a day for at least 60 consecutive days.